Washington D.C. Detective and forensic psychologist, Dr Alex Cross, Morgan Freeman, is devastated to learn that his niece Naomi, a college student in Durham, North Carolina, has been missing for four days. Despite his family's anxiety, Cross travels to Durham to investigate, determined to find her.
Upon arrival, Cross meets with local police and learns that multiple young women, including Naomi, are missing. He collaborates with Detectives Nick Ruskin and Davey Sikes, as well as FBI agents. Together, they visit a crime scene in the woods where the body of one of the missing women has been found, brutally murdered and tied to a tree, heightening Cross's fears for Naomi's safety.
Meanwhile, Dr. Kate McTiernan, a doctor and kickboxer, Ashley Judd is abducted from her home by a masked man who calls himself Casanova (Casanova Cary Elwes). She wakes up in a stone-walled room, heavily sedated, and is told by Casanova that he admires her talents and promises she won't suffer if she complies with his rules. Kate, however, is determined to escape. She discovers other women are held captive with her.
Kate eventually manages to overpower Casanova during one of his visits and escapes into the woods, jumping off a cliff into a river to ensure her freedom. She is found and taken to a hospital, where she recovers and agrees to help Cross in his investigation. She provides vital information about her captivity and describes Casanova.
Cross investigates further and discovers that a plastic surgeon in California, Dr. William Rudolph, had suspiciously ordered a large quantity of Sistol, a benzodiazepine drug, which was used to sedate the captives. Travelling together to California, Cross and Kate join forces with Sampson, Cross' partner, and Henry, an LAPD Detective, to begin surveilling Rudolph.
After staking out Rudolph's home, they follow him to a remote cabin in the woods. The investigation intensifies when they follow Rudolph to a nightclub. Kate, upon seeing Rudolph caress a woman's cheek, recognizes his touch and, believing he is Casanova, alerts Cross. Rudolph takes the woman from the nightclub to his cabin, where a chase ensues when the group hears her screaming, during which Rudolph escapes after shooting one of Sampson’s men and injuring Cross.
At Rudolph's home, the police uncover the identity of a second killer, named by the press as the Gentleman Caller. This killer is also involved in the abductions and is working in conjunction to and competition with Casanova. The two operate bicoastally, abducting women within days of one another and sharing images of their captives for the other to see. The police also discover a hidden freezer which contains mutilated body parts of his victims, distinguishing the Gentleman Caller's MO from Casanova's.
Back in North Carolina, with the help of Naomi's boyfriend who is familiar with the area, Cross locates the hideout where the women are being held. Concurrently, Rudolph has also travelled to North Carolina and has broken into Casanova's lair. He enrages Casanova when he tries to undermine his control of Naomi and the other captive women, who shoot at Rudolph, but Rudolph intentionally misses. Upon hearing Cross enter the hideout, Casanova tells Rudolph to flee. In a climactic confrontation, Cross and the police rescue the captives, including Naomi. Rudolph is killed by Cross in an ensuing chase, but Casanova escapes.
The FBI raid the hideout and locate Casanova's fingerprints. Finally feeling safe, and with the belief that Casanova will be identified within a day, Kate invites Cross to dinner before he returns back to D.C. Before Cross is due to arrive, Detective Ruskin arrives at Kate's home to check in on her. She welcomes him inside and, whilst her back is turned, he cuts her phone line.
In the meantime, Cross recognizes a similarity between Casanova's handwriting and Ruskin's signature. Realizing Ruskin is Casanova, Cross rushes to save Kate. Ruskin, now revealed as Casanova, attempts to rape and kill Kate. A fight ensues, breaking a gas line in the kitchen. Realising this, Ruskin takes out a lighter, threatening to ignite it. Cross arrives just in time to intervene. In the final struggle, Cross shoots Ruskin through a milk carton, preventing him from causing an explosion in Kate’s house. Casanova is finally dead, and Cross and Kate embrace as the police arrive.
