As a teenage boy in 1975 Boca Raton, Florida, a future serial killer calling himself "Casanova" kills his first four victims. Elsewhere in 1981 Chapel Hill, North Carolina, another killer calling himself "The Gentleman Caller" kills a young couple on a lake.
Years later, Casanova leaves a young woman to die in the woods. Around the same time, Washington Police Detective Alex Cross comes home to find several relatives waiting for him and is informed that his niece, Naomi "Scootchie" Cross, currently a student at Duke University in Durham, North Carolina, is missing. He travels to North Carolina with his partner Sampson and they meet Detectives Nick Ruskin and Davey Sikes, who tell them that the FBI and DEA are involved and that eight to ten women are missing, all from different states; all have received notes from someone calling himself Casanova. Around the same time, Casanova abducts another woman, Dr. Kate McTiernan, and makes her part of his harem of young, attractive, and exceptional women.
In Los Angeles, reporter Beth Lieberman is working on a serial killer story about "The Gentleman Caller", who has just raped and murdered a fourteen-year-old girl. He threatens "bonus kills" if his letters are not published in her newspaper. FBI agent Kyle Craig meets Lieberman in LA.
Casanova plans to kill Kate McTiernan because she broke the rules, but she fights him and manages to escape, running into a forest and jumping off a cliff into the river below. Meanwhile, Cross discovers that one of the Gentleman Caller's notes published in the Los Angeles Times mentions Naomi. After contacting Lieberman and her editor-in-chief, he learns that Casanova and the Gentleman Caller are communicating as coast-to-coast serial killers. Back in the hospital, Cross discovers Kate McTiernan was drugged with Marinol, which leads them to believe that Casanova is a doctor or a pharmacist. Agent Craig informs them that Beth Lieberman was murdered by the Gentleman Caller. Her files contained hints to a possible suspect, Dr. William Rudolph from Los Angeles. Cross and McTiernan travel there with Craig, and McTiernan rules Rudolph out as Casanova, meaning he must be the Gentleman Caller. A manhunt for the killer begins, but he gets away several times and vanishes. A search of his apartment uncovers a picture of him with one Dr. Wick Sachs; notes on the back identify Sachs as "Casanova".
Cross and Sampson discuss a theory that the girls are being held in an underground house, built in an area that was part of the Underground Railroad. Sachs is a professor at Duke and known as the campus skeleton, as well as a suspect when two students were murdered in the early 1980s. Later Ruskin and Sikes ask Cross for help in catching Casanova, whom they believe to be Sachs.
Rudolph reminisces how he met Casanova, who had known Rudolph had killed the young couple. They shared their experiences and formed a bond. When they reunite, they decide to work together to take down Cross. They first attack McTiernan after she returns to her home, leaving her seriously wounded. Cross notices that this attack is different from the first one and suspects both men worked together. The next day, Dr. Sachs is brought in for questioning. Cross attacks him physically, noticing that Sachs is not very strong, and is sure that he is not Casanova. However, the FBI arrests Sachs nonetheless after finding evidence pointing to him. Sampson and Cross head to the forest again, taking a hand-written map given to them by an Underground Railroad historian. In a previously unsearched area, they find the underground house with the captive women. However, the two killers have been watching them and assault them, seriously injuring Sampson. Cross fires at them, hitting one in the shoulder. The two leave, steal a truck and take off. Cross goes after them, and eventually forces them to split up; in the following gunfight, he kills Rudolph. The surviving women, including Naomi, are reunited with their loved ones.
Cross looks for clues and soon thinks he knows who Casanova is. He keeps the information from Agent Craig and decides to go on his own stakeout. He follows Detective Sikes, positive that he is Casanova, looking for a new woman to kidnap. He snoops outside a house where Sikes has gone in. Sikes sees him and the two get into a fight. The woman turns out to be Sikes' mistress, an affair the FBI knew about.
A while later, while visiting McTiernan, Cross goes jogging and finds a dead FBI agent. He runs back to the house where Casanova, who is revealed to be Sikes' partner, Detective Nick Ruskin, hits him with a stun gun. With Cross down, Casanova heads for Kate, but Kate fights him and takes him down. He takes out his gun to shoot her, but Cross gets up in time to shoot and kill him in self-defense. Cross and McTiernan later go their separate ways even though they have become close friends. Once back in Washington, Cross and Sampson soon get a new case.