In a Mexican cantina across the border from El Paso, Harry Hannan, Roy Scheider is romancing his wife Dorothy Hannan, Sandy McLeod. He spots an informant he is due to meet in a few days. Realizing he is about to be attacked, he shoves his wife to the ground and opens fire on the informant's companions who return fire and flee the restaurant. Dorothy is killed in the attack, and he suffers a nervous breakdown. He spends five months in a Connecticut sanitarium before being released.
On his way back to New York City, Harry stumbles and nearly falls into the path of an express train. He goes to the makeup counter at Macy's Herald Square to retrieve his next assignment, but the assignment slip inside the lipstick case is blank. He accosts his contact who assures him that the agency probably does not have any work for him.
Back at his apartment, he finds it occupied by a doctoral student named Ellie Fabian, Janet Margolin. She explains that she had a sublet arranged while she was in the last semester of her studies at Princeton University. She gives Harry a note that contains only a few Hebrew characters that he cannot read.
Paranoid that he is being targeted by his own agency, Harry visits his supervisor Eckart, Christopher Walken. Eckart insists that the agency has higher priorities and that Harry is not yet ready to return to the field.
Harry takes the Hebrew note to a local rabbi who can only partially decode it, and explains that it means "Avenger of Blood." The rabbi then calls Sam Urdell, Sam Levene, and informs him that Harry has visited him. Harry notices that he is being surveilled, loses the tail, and goes to the American Museum of Natural History, where Ellie is working.
He gives her some money and urges her to stay in a hotel, because he fears she will be accidentally targeted. He then visits his wife's grave, where he confronts her brother, Dave Quittle, Charles Napier. Afterwards, Quittle visits Eckart, who orders Harry's murder.
Ellie stays in the apartment despite Harry's request. Ellie suggests that they take the note to her friend at Princeton who specializes in Hebrew studies. When Harry wakes from a nightmare, he tells Ellie about the death of Dorothy. He takes a prescription pill, but spits it out, realizing that it is cyanide. The next morning, they leave for Princeton. On the train, Ellie tells Harry about her grandmother, when Harry notices Quittle, and an old man, watching them.
At Princeton, Richard Peabody, John Glover, decodes the note for Harry. Peabody has accumulated several notes, all attached to very peculiar murders. Harry is the first one to have received the note and lived. He also relays a message that someone wants to meet Harry in the bell tower courtyard the following day.
In the courtyard, Harry is lured into a trap by Quittle. Harry manages to kill Quittle during a shootout in the bell tower, and then encounters Sam Urdell, the old man on the train. Sam explains that he is part of a committee investigating the blood murders. They investigate the various clues, and they piece together that Harry's grandfather owned a brothel on the Lower East Side of Manhattan.
In a hotel at Niagara Falls, Ellie is dressed as a prostitute and lures Bernie Meckler, Andrew Duncan, into a bathtub with her. As she has sex with Meckler, she drowns him. As Harry and Sam put together their information, they are led back to Princeton. Harry realizes that Ellie is the one murdering men, on behalf of victims of white slavery like her grandmother. They drive up to Niagara Falls, where they have an emotional confrontation. She tries to kill him, but confesses that she loves him. He is conflicted, but he tells her that he will turn her in. Ellie knees him in the groin and runs away; he chases her through the Robert Moses Niagara Power Plant. She escapes onto a tour bus and he steals another tour bus and follows her to the Journey Behind the Falls, where he chases her through the tunnels until they have a final confrontation at the edge of the falls. They break through the railing and Harry grabs Ellie, but she struggles and takes a deadly plummet.
