After Gabriella Betarrini and her sister, Evangelia, travel back in time to the 1300s Italy and return to present-day Italy, they are found in a restricted archeological site and brought to their mother, an archeologist working at the site. Gabi and Lia tell their mother about entering a tomb in the restricted area and finding two handprints on the wall that matched their hands perfectly. When they touched the handprints in unison, they were transported back in time. Their mother doesn't believe them but is willing to but aside her doubts until they show her the tomb. After the three sneak back to the tomb and examine the handprints, their mother wants the girls to take her with them to medieval Italy. But Lia is concerned about going back. They returned to present day because Gabi was injured in battle and then poisoned. Traveling through time appears to have healed her. Lia fears returning could make Gabi sick again. Gabi convinces Lia to return.
In ancient Italy, Gabi remains healed, which is a relief to Lia and their mother. Inside the tomb, there are clothes for the sisters, weapons and a note from Marcello Forelli. Gabi met Marcello on her first trip to the 1300s. The second son of a wealthy lord, he sheltered Gabi and soon fell in love with her. The note tells her to come to his castello, which is nearby, but to be careful of the enemies in the woods that would consider her capture a great prize. Before leaving the tomb, Lia and Gabi tell their mother the cover story they concocted on their first trip. They are from Normandy, and their mother is a merchant who deals in ancient artifacts. When she went missing, the sisters traveled to Toscana to search for her.
With weapons at the ready, the women head for Castello Forelli. They left in summer but have returned in autumn, indicating they didn't travel back as far as they intended. When the castello comes into view, their mother is convinced that everything they've said is true. She realizes that Gabi almost died. Gabi comforts her, saying that being in this time period makes her feel alive. Lia believes Gabi feels alive because she's fallen in love with Marcello. Gabi concedes that Marcello might be the reason.
They are interrupted by the sound of approaching horses. Drawing their weapons, the three women hide and wait to see who approaches. A group rides past, headed toward Firenze. Behind them at a safe distance are Marcello and his men.
The women reveal themselves, and Marcello races to Gabi. After he embraces her and they share a kiss, Marcello introduces himself and his cousin Sir Luca to the girls' mother. He offers them shelter at Castello Forelli, and the women accept. On the journey to the castello, Gabi asks about the men Marcello was following. He says they are spies from Firenze, who are searching not only for a weakness in the Forellis' defense, but also for Gabi and Lia. On their previous visit, the sisters helped the Forellis capture the neighboring castle, Castello Paratore. Stories of the She-Wolves of Siena, as the sisters are now known, have spread, inciting Firenze's anger. War may be on the horizon.
At the castello, Gabi sees Lady Romana Rossi. Romana was once engaged to Marcello, but when Marcello fell in love with Gabi, the two broke off their engagement. Romana remains at the castello because she is now engaged to Fortino, Marcello's older brother. In the three months Gabi was gone, Lord Forelli died, making Fortino the new lord. Gabi doesn't trust Romana and believes her engagement is a power play that isn't motivated by love. She also suspects Romana as being the one who previously tried to poison her.
That evening, Fortino throws a feast to celebrate the Ladies Betarrini and their return. He tells them that he plans to bring them to Siena, despite Marcello's concern that they could be attacked on the journey. After the feast, Marcello and Gabi go off alone. They share a passionate kiss in the shadows before discussing Fortino and Romana's engagement. Marcello asks Gabi if she plans to stay in his time permanently. She doesn't have an answer, saying there is much she has to consider. He is disappointed and asks if she shares his feelings. Gabi confesses her love.
On their second morning, Marcello and his men prepare to help the farmers who have joined in the fight against Firenze and left their harvest to rot. The men intend to help bring in the crops. Gabi and Lia join the men despite Marcello's protests. While in the fields, Sienese soldiers approach, led by Captain Rossi, Romana's cousin. He informs Marcello that he is needed in Siena in three days to attend a ball. Diplomats from Firenze will attend, and the She-Wolves of Siena will be honored. Marcello doesn't wish to go but reluctantly consents.
In Siena, they arrive to adoring crowds. Marcello and his men lead the women to Lord Rossi's home where they will stay during their visit. That evening at the feast, Gabi meets Lord Rodolfo Greco, one of the diplomats from Firenze. After the feast, the Ladies Betarrini are presented to the people. Lord Paratore, the man who captured Lia on the sisters' first trip back in time, is presented to them, and Gabi is asked to pass judgment on him for his crimes. She is given the option to kill him or exchange him for 100 Sienese men imprisoned by Firenze. As she deliberates, Lord Paratore begins shouting that the Ladies Betarrini are not who they claim. To discredit his words, Gabi declares that he's been listening to lies. She demands he be traded, but to prevent him from listening to more lies, his ears must be cut off. The sisters escape the plaza as Gabi's sentence is being carried out. Lia comforts Gabi, telling her she only did what she had to. In the middle of the night, Gabi wakes to find Lord Rossi in her room. He confronts her about her identity and reveals that her involvement with Marcello, which resulted in his broken engagement to Romana, humiliated his family. He promises he will find out the truth about her and threatens to move against her if she gets in the way of Romana and Fortino's marriage. When Lord Rossi leaves, he passes Marcello, who's come to check on Gabi. She tells him what Lord Rossi wanted and asks whether he trusts the Rossi family, specifically Romana. Marcello swears he trusts them, but tells Gabi to lock the door behind him as he leaves.
After returning to Castello Forelli, Gabi and Lia go with Marcello and Luca to harvest the grapes, leaving their mother at the castello. While they are in the fields, Signore Giannini, the owner of the farm, arrives after being released in exchange for Lord Paratore. Gabi sees that he shows symptoms of the plague. After questioning him, she realizes that Firenze released only prisoners who showed signs of illness. To prevent spreading the plague, the group decides to travel to Orci villa, a home belonging to Marcello's family, where they will wait 10 days to see if any of their people are infected. They travel under cover of darkness to keep Fiorentini soldiers from seeing them. Despite the cover of night, a group of soldiers from Firenze, led by Lord Greco, find them and attack. Marcello commands Gabi to fight to the death if need be. During the battle, Gabi faces Lord Greco. He demands that she and Lia denounce Siena and swear allegiance to Firenze. She refuses and continues to fight, but he overpowers her. Desperate, she reveals that they were exposed to the plague. Afraid of the disease, Greco calls off the attack, which allows the group to continue to the villa.
After settling into the villa, soldiers from Siena arrive to protect them. Gabi and Lia discover that Luca is showing signs of the plague. They wash his sores with vinegar and use cold water to reduce his fever. While Lia tends to Luca, Marcello takes Gabi aside and tells her that Firenze has cut off further Sienese reinforcements. He shows her a hidden passage that leads out of the villa and commands that the sisters escape if the soldiers outside the villa can't protect them. Unfortunately, the passage will take them into the borders of Firenze. When the villa comes under attack, Luca and Marcello join the sisters in fleeing through the tunnel. During their escape, they come across a cave-in. With no other option, they move the stones and try to make it appear as if the cave-in happened behind them. When soldiers make it to the cave-in, they assume Gabi, Luca, Lia and Marcello escaped above ground. The four continue, coming to an underground lake. Keeping to the shallow parts, they travel across it. Luca is delirious and needs assistance. The sisters know he needs help, but because of their fame, they are a danger to the men. The group decides to split up. Marcello and Luca will pose as Fiorentini loyalists and enter the enemy camp seeking help, while Lia and Gabi travel to a system of caves about a mile away. Marcello promises to return for them as soon as he can.
Gabi and Lia follow Marcello's directions and eventually, they recognize the ruins of an Etruscan necropolis they visited in their time. When they hear horse hooves in the distance, they decide to seek shelter in the necropolis. They climb a cliff, trying to reach the necropolis' entrance. Before they can make it inside, Lord Greco and his soldiers find them. Gabi pretends to surrender before making a run for it, and she and Lia manage to lose Greco. Familiar with the area, the sisters head to another set of tunnels built by the Etruscans. They leave a dummy trail for Greco and his men before taking shelter deep in the tunnels.
Later, they emerge by a road occupied by hundreds of soldiers marching toward Siena. The girls keep to the hills to avoid the road and eventually come to a farm, where they stop for a drink from a well. The woman who owns the farm finds them. Her husband was conscripted, leaving their grapes to rot on the vine. Lia and Gabi agree to help harvest the crop the next day in exchange for food and shelter for the night. The sisters wake to hear Lord Greco and his men at the farm and quickly hide in the house's rafters. The farmer's wife tells the soldiers that she gave the women shelter, but she doesn't know where they went. After the men leave, the woman gives the sisters some of her husband's clothes as a disguise so they can escape. But the sisters insist on staying and bringing in the grape harvest as they promised. While they are working in the field, a group of soldiers come. They think Gabi and Lia are boys and conscript them into the army. The girls go with them, lying low as they march closer to Siena.
After reaching camp in the evening, they are instructed to rest for the morning's battle. Instead, Gabi sneaks into a nobleman's tent to see if she can discover Firenze's battle plans. Looking at a map, she sees Lord Paratore's name on it. She also sees that Castello Forelli has been renamed Castello Rossi. Sept. 21 and 22 are marked on the map as days of attack. Lia whistles, indicating that soldiers are headed Gabi's way. She tries to flee but accidentally knocks a candle over. When the tent catches fire, she cuts her way out of the tent. Lord Paratore recognizes Gabi and alerts the soldiers. As the sisters flee to the woods, they run into a massive pile of boulders and start climbing them. Coming down on the other side, they loosen a boulder and create a rockslide. When Gabi injures her hamstring and can't continue, she insists that Lia go and warn Siena about the coming attack and the Rossis' betrayal. Lia flees, and Lord Greco captures Gabi.
Lord Greco sends for a physician, who bandages Gabi and gives her something for the pain. In the morning, Gabi faces the journey to Firenze. When they reach Firenze, people gather to see Gabi brought into the city. They throw rotten food at her, but Lord Greco stops them from throwing stones. He tells the people she mustn't be harmed until she faces judgment. She is brought before the rulers and asked if she will help them and betray Siena. They want her to get them into the city and assemble the rulers of Siena so that they can be killed. She refuses, and they decide to hold her for ransom. They want Marcello to exchange Castello Forelli and Castello Paratore for her. Until he comes for her, she is to be on public display. Lord Greco escorts her, and much to her surprise, brings her food. He reveals a tattoo on his arm. The tattoo matches one Marcello has on his arm. He tells her to remember she is not alone. After she is brought to a public plaza, she is forced inside a cage and hoisted up for all to see.
Gabi spends the day in the cage as the city celebrates below her. The guards refuse to let her down to relieve herself. By nightfall she is so desperate that she urinates in the cage. As another day passes without food or water, she knows she will die if help doesn't come within a day. On her second night, she wakes to find Marcello and Lord Greco working to free her. Luca, who has fully recovered, and Lia are there as lookouts. As she is freed, the guards notice the escape attempt and sound the alarm. Lord Greco distracts the guards; Gabi, Marcello, Lia and Luca escape. They head to the river, intending to use that as their escape route. They make it out of the city and travel through the forest to an abandoned cottage where they spend the night. In the morning, Gabi asks Marcello how he knew about the cottage. He reveals that Lord Greco directed him there, and the two men, along with Luca and a number of others, are members of a secret brotherhood whose bond of loyalty surpasses that of Firenze or Siena. Gabi learns that Lia made it back in time to warn Siena of the coming soldiers.
At dusk the next day, the foursome sets off for the two-day journey to Siena. When they return, they find that Castello Paratore and Castello Forelli have fallen to Firenze. They head to the Sienese camp where the sisters are reunited with their mother. She tells them that the castello was taken with the help of traitors on the inside. They also learn that Fortino is missing. Soon after their return, Lord Paratore and a group of soldiers approach the camp seeking Marcello. He rides out to meet them and finds that they have Fortino. They want immediate surrender, retreat and the Ladies Betarrini in exchange for Fortino. Marcello refuses. In the morning, he rides out to battle, leaving Lia and Gabi under Luca's watch. The sisters discuss whether they want to stay in medieval Italy forever. Gabi does, as long as Lia and her mother are with her. Lia still isn't sure. Their mother wonders if they could travel back to the future, to the time just before when their father died and save him. They worry that doing so might change their futures.
Luca leads the women south to safety. A scout rides up to them, telling Luca that the battle was a trap and that Marcello and his men are vastly outnumbered. Knowing Firenze wants the She-Wolves more than Marcello, Gabi convinces everyone to use them as bait to draw the soldiers away from Marcello. When they are spotted, they will return to the tomb with the handprints and travel home. They manage to divert Lord Paratore and his men away from the battle. The soldiers give chase, but the Ladies Betarrini make it to the tomb and travel back to their own time.
Back home, they decide to try and save their father. They manage to return to the time before their father died and find him at a nearby archeological site. He is initially confused to see his two daughters looking grown up, but he returns to the tomb with them and his wife. He listens to their tale and is willing to suspend disbelief until after they've tried time travel. They plan to return to medieval Italy. The family, now reunited, declares they will move forward as one.