In the late 1960s, San Francisco is gripped by fear as a serial killer, self-dubbed "Zodiac," begins a terrifying spree. Taunting the police with cryptic letters, ciphers, and bloodstained clothing, Zodiac claims numerous lives and generates a media frenzy. The killer's cryptic communication, which is sent to newspapers, challenges readers and investigators with encoded messages, claiming that they will reveal his identity if deciphered. As the killings continue, the case becomes an obsession for three men: Robert Graysmith, a cartoonist at the San Francisco Chronicle; Paul Avery, the newspaper's crime reporter; and Dave Toschi, a San Francisco Homicide Inspector. Graysmith, with a penchant for puzzles and codes, finds himself deeply enmeshed in the case, propelled by a desire to solve the mystery that consumes the city.

The investigation's complex nature draws Graysmith deeper into a web of clues and false leads. Meanwhile, both Avery and Toschi encounter professional turmoil and personal demons as they delve into the darkness of the case. The strain of the unsolved crimes wears heavily on them, with Avery's flair for journalism and Toschi's dogged police work often clashing yet driven by the same goal: to stop Zodiac. The killer's game of cat and mouse escalates, thrusting the trio into an increasingly perilous hunt. Each man becomes relentless in his pursuit of justice—or closure—as they face the chilling realization that Zodiac might always be one step ahead.