On July 4, 1969, an unknown man attacks Darlene Ferrin and Mike Mageau with a handgun at a lovers’ lane in Vallejo, California. Only Mike survives.

One month later, the San Francisco Chronicle receives encrypted letters written by the killer calling himself the “Zodiac,” who threatens to kill a dozen people unless his coded message containing his identity is published. Political cartoonist Robert Graysmith, who correctly guesses that his identity is not in the message, is not taken seriously by crime reporter Paul Avery or the editors and is excluded from the initial details about the killings. When the newspaper publishes the letters, a married couple deciphers one. In September, the killer stabs law student Bryan Hartnell and Cecelia Shepard at Lake Berryessa in Napa County; Cecelia dies two days later.

At a bar, Avery makes fun of Graysmith before they discuss the coded letters. Graysmith interprets the letter, which Avery finds helpful, and he begins sharing information. One of Graysmith’s insights about the letters is that the Zodiac’s reference to man as “the most dangerous animal of them all” is a reference to the film The Most Dangerous Game, which features the villainous Count Zaroff, a man who hunts live human prey.

Two weeks later, San Francisco taxicab driver Paul Stine is shot and killed in the city’s Presidio Heights district. The Zodiac killer mails pieces of Stine’s bloodstained shirt to the Chronicle along with a taunting letter. San Francisco police inspectors Dave Toschi and his partner Bill Armstrong are assigned to the case by Captain Marty Lee, and work closely with Vallejo’s Jack Mulanax and Captain Ken Narlow in Napa. Someone claiming to be Zodiac continues to send taunting letters and speaks on the phone with lawyer Melvin Belli on a television talk show hosted by Jim Dunbar.

In 1971, Detectives Toschi, Armstrong, and Mulanax question Arthur Leigh Allen, a suspect in the Vallejo case. They notice that he wears a Zodiac wristwatch, with the same logo used by the killer. However, a handwriting expert insists that Allen did not write the Zodiac letters, even though Allen is said to be ambidextrous. Avery receives a letter threatening his life; becoming paranoid, he turns to drugs and alcohol. He shares information with the Riverside Police Department, angering Toschi and Armstrong. The case’s notoriety weighs on Toschi, who is unable to sit through a Hollywood film, Dirty Harry, loosely based on the Zodiac case.

In 1978, Avery moves to the Sacramento Bee. Graysmith persistently contacts Toschi about the Zodiac murders, and eventually impresses him with his knowledge of the case. While Toschi cannot directly give Graysmith access to the evidence, he provides names in other police departments where Zodiac murders occurred. Armstrong transfers from the San Francisco Police homicide division, and Toschi is demoted for supposedly forging a Zodiac letter.

Graysmith continues his own investigation, profiled in the Chronicle, and gives a television interview about the book he is writing about the case. He begins receiving phone calls with heavy breathing. As his obsession deepens, Graysmith loses his job, and his wife Melanie leaves him, taking their children. Graysmith learns that Allen lived close to Ferrin and probably knew her and that his birthday matches the one Zodiac gave when he spoke to one of Belli’s maids. While circumstantial evidence seems to indicate his guilt, the physical evidence, such as fingerprints and handwriting samples, do not implicate him. In 1983, Graysmith tracks Allen to a Vallejo Ace Hardware store, where he is employed as a sales clerk; they stare at each other before Graysmith leaves. Eight years later, after Graysmith’s book, Zodiac has become a bestseller, Mike Mageau identifies Allen from a police mugshot. Final text indicates that Allen died before he could be questioned and that the case remains open.