Dr. Alex Cross is a psychologist and police lieutenant who lives in Detroit with his wife Maria and their children. After learning Maria is pregnant, Cross considers accepting a job as an FBI profiler in Washington, D.C. Meanwhile, a man participates in an underground fighting match and seduces businesswoman Fan Yau. The man is invited to Yau’s house, where he kills her after injecting her with TTX.
At the crime scene, Cross finds a charcoal sketch left behind by the killer in the style of the artist Picasso, leading to the murderer being nicknamed after him. While examining the sketch, Cross deduces that Picasso’s next target is German businessman Erich Nunemarcher. Picasso attempts to kill Nunemarcher but is foiled by Cross, and escapes after being shot by Cross’s partner Tommy Kane. Cross deduces that Picasso also plans to target billionaire CEO Giles Mercier.
As revenge for foiling his attack on Nunemarcher, Picasso attacks Cross and Kane’s colleague, Monica Ashe, torturing her to death. Picasso then tracks down Cross, who is on a date with Maria, and kills her with a sniper rifle.
Picasso targets Nunemarcher and Mercier at a conference, killing Nunemarcher and seemingly Mercier. Cross and Kane track Picasso to the abandoned Michigan Theater. As Cross and Picasso fight, they fall through the crumbling theater ceiling. Cross kicks Picasso off the ceiling, killing him and avenging Maria. Kane helps pull Cross to safety.
Cross deduces Picasso’s employer was Mercier himself. Having embezzled money from his clients, Mercier asked for Yau and Nunemarcher’s help to fake his death and flee to Bali, then hired Picasso to eliminate them and a double pretending to be the real Mercier. After Cross frames Mercier for drug smuggling, Mercier is arrested in Indonesia, where he will be condemned to death by firing squad. Having avenged Maria’s murder, Cross decides to accept the job offer from the FBI and moves to Washington with his family.