The film starts on July 4, 1969, with the Zodiac killer's second attack. After shooting Darlene Ferrin and Mike Mageau at a lovers' lane in Vallejo, the killer calls 911, and reports his actions. Mageau survives while Ferrin dies from her injuries.
Four weeks later, a letter written by the Zodiac arrives at the San Francisco Chronicle. An encrypted letter is included, as well as a demand that the newspaper publish the letter or the Zodiac will kill again. Similar demands with different encrypted letters, have also been sent to the Vallejo Times and the San Francisco Examiner. Paul Avery (Robert Downey, Jr.), a Chronicle crime reporter, soon begins to investigate for the newspaper. The encrypted letter catches the eye of the Chronicle's political cartoonist, Robert Graysmith (Jake Gyllenhaal). Eventually, the encryption is cracked by a history teacher in Salinas, California. However, there are some left-over letters that haven't been deciphered, and Graysmith begins trying to figure them out, catching Avery's attention. Along with the extra symbols, is a symbol that Avery says looks like a "gun sight."
The Zodiac killer strikes again in September of 1969, confronting and stabbing Bryan Hartnell and Cecelia Shepard (Pell James) at Lake Berryessa in Napa County. Shepard dies as a result of the attack, while Hartnell survives. Zodiac then sends a new letter to the Chronicle, in which he calls man "the most dangerous game of all." Robert sparks to the line, recalling it as a line from a film, based on a book called "The Most Dangerous Game."
Soon afterward, San Francisco taxicab driver Paul Stine is shot and killed in the city's Presidio Heights district. San Francisco police detectives Dave Toschi (Mark Ruffalo) and his partner Bill Armstrong (Anthony Edwards) are assigned to the case, but the actions of the killer (whom they do not know is the Zodiac at the time), seem perplexing.
It is shortly after this that the Chronicle receives a new Zodiac letter, with a piece of the cab driver's bloody shirt. The Zodiac also states in the letter, that he plans to attack city school buses. Toschi and Armstrong soon find themselves liaising with other detectives such as Jack Mulanax (Elias Koteas) in Vallejo and Ken Narlow (Donal Logue) in Napa, reviewing the evidence on Zodiac. While the SFPD was able to get a partial fingerprint from the taxi cab crime scene, Narlow tells how a ranger accidentally destroyed the Napa crime scene. However, they did find "Wing Walker" boot prints on the ground, with the footwear only able to be purchased with a Military ID. Armstrong attempts to get an interview with Michael Mageau (the survivor of the Zodiac's second killing), but is informed by Vallejo PD that he is no longer in town. The different police departments also find themselves struggling to communicate between each other, given that much of the sending of material evidence has to be done exclusively through postal mail.
In their own little conversations afterwards, Avery and Greysmith, as well as Toschi and Armstrong, question the Zodiac's motives. The cab driver is his first killing that doesn't involve a couple...leading the two groups of men to believe he's trying to break his pattern.
Soon afterward, the Zodiac ( or someone claiming to be him), requests to call into an early morning talk show, and speak with celebrity lawyer Melvin Belli (Brian Cox). A deep-voiced man who goes by the name of "Sam" calls in. Giving into Melvin's request to meet, Sam says to go to a church in Daly City. Melvin and the SFPD rush to the scene, but Sam is a no-show, and it is soon revealed that the caller was someone from a mental institution. Even Bryan Hartnell (the survivor of the Zodiac's third killing), confirms the voice does not belong to the man he encountered at Lake Berryessa.
Another letter soon arrives at the Chronicle, taunting the police, and including instructions for creating an explosive device. It is after this that Avery and Graystone have a conversation about their interest in the letters. Graystone explains his liking of puzzles, that made the challenge to solve the Zodiac's ciphers intriguing. He also tells of a number of different codes he found that were included in the letters...including one referred to as "the Zodiac alphabet."
The Zodiac sends a letter to Melvin Belli for Christmas of 1969, and through the Spring and Summer of 1970, sends a number of letters to the Chronicle, once again taunting the police, and claiming responsibility for a number of incidents. The Chronicle soon decides to stop publishing the letters, once Avery calls into question just how truthful the Zodiac is. Paul also confides to Graysmith, that the "gun sight" symbol on the letters, appears to have been copied from the symbol for the Zodiac brand of watch.
Avery writes a number of unflattering stories about the Zodiac, and is "rewarded" for this with a personal letter from the Zodiac, along with a piece of the cab driver's bloody shirt. Paul attempts to find out more about the Zodiac, and meets with an unspecified source in Riverside, California. From this, Avery believes he has found evidence of the Zodiac's first murder victim (predating the 1969 shooting of Darlene Ferrin and Mike Mageau).
This sends Toschi and Armstrong to Riverside to investigate. The evidence seems similar, but they rule out it being an exact match to their killer. However, Paul Avery's stories convince much of the viewing public, infuriating Toschi.
Avery's article soon brings all sorts of people to Toschi and the SFPD, many of them claiming to know the Zodiac's identity. Of all the interviews, one about a man named Arthur Leigh Allen (John Carroll Lynch), sounds very promising. Toschi, Armstrong and Mulanax then go to question Arthur, though turn up nothing concrete. They interview several of Arthur's family, who turn over handwriting samples for study. However, handwriting expert Sherwood Morrill's review of the letters, shows no connections. Eventually, Toschi and is told by Arthur's family that he has moved to Santa Rosa. A warrant is issued by the Santa Rosa PD, and Toschi and Armstrong search Arthur's trailer. They find a number of weapons, and soon confront Arthur when he arrives home. However, after getting a new handwriting sample and checking his prints, nothing of Arthur's matches any of the information on file for Zodiac, infuriating Toschi that his best lead didn't pan out.
Trying to unwind, Toschi and his wife go to see the film "Dirty Harry." After it ends, Toschi meets Graysmith in the lobby. Robert assures Toschi that he'll catch the Zodiac, but Toschi seems very unsure.
Four years later, it is 1975. In that time, Graysmith has remarried, and has restarted having a family. Paul Avery meanwhile, has had his sanity take a nose-dive, quitting the Chronicle and going to work for the Sacramento Bee. Dave Toschi is thrown for a loop when his partner Bill Armstrong tells him he is quitting homicide, and moving over to the fraud department.
Throughout this time, the Zodiac has been silent. When Graysmith's wife Melanie (Chloë Sevigny) mentions all the Zodiac stuff he's collected over the years, Robert visits Paul, and tells him about wanting to write a book about Zodiac. However, Robert's hopes are dashed when Paul tells him that he no longer has any of his stuff on the killer, and chastises the curious man.
Robert next inquires to Dave Toschi. Though Toschi claims he can't help Robert, he quietly tells him to inquire to Ken Narlow in Napa. Narlow allows Robert to look through the Napa Police's evidence on the case Darlene Ferrin and Mike Mageau.
Robert then tells Toschi that Darlene seemed to have a number of admirers, and it's possible the person who is the Zodiac, may have been one of them. Plus, there were suspicious phone calls with heavy-breathing on the line, made to a number of Darlene's relations on the night she was murdered, further making Graysmith believe the killer knew her. Robert claims he needs to find Darlene's sister, but Toschi also recommends he inquire to Melvin Belli.
Robert pays the lawyer a visit, and in an interesting discussion with one of his housekeeper's, is informed that the Zodiac talked to her. Mr Belli was not home, and the Zodiac informed the housekeeper that he "had to kill, because it was his birthday" that day.
This evidence allows Robert to narrow down the dates to December 18th through the 20th, and while Toschi recommends he check the Department of Justice for information, he doesn't get much help. It is soon after, that Robert gets a call at home, from a man who claims that the Zodiac's real name is Rick Marshall, and a man named Bob Vaughn has film canisters with evidence showing Rick is the Zodiac.
Robert also goes to talk to Sherwood Morrill about fingerprints and handwriting samples. During the talk, Sherwood tells how a man named Wallace Penny, told him a man named Rick Marshall was the Zodiac, shocking Robert that the man who called him, also spoke to Sherwood!
Back at the SFPD, Toschi is called in when the department receives their first Zodiac letter in four years. However, some assume that Toschi forged the letter, and the suspicions lead to him being kicked off of the homicide division. Robert attempts to speak to Toschi, but Dave refuses to answer any questions about Rick Marshall.
Robert then goes up to Napa, and speaks with Ken Narlow. Narlow tells how he had interviewed Rick Marshall, but was never able to get fingerprints of handwriting samples from him. Hoping to find Marshall, Robert calls up Morrill, and gets the number of Wallace Penny.
Wallace sends Robert one of the posters he claims Rick drew for a silent movie house. Morrill examines it, and sees some small similarities to Zodiac, but needs more information to review.
By now, the case has consumed Robert's life. He loses his job at the Chronicle, and his wife takes the kids and leaves, fearful that the Zodiac may target their family. Someone has also been calling Robert's phone number, breathing heavily, and hanging up. Robert continues trying to track down Darlene Ferrin's sister Linda for help, but also inquires to a Bob Vaughn for help. Vaughn knew Rick Marshall as a theater projectionist a long time ago, though when Robert mentions the posters they are looking through for evidence, Bob claims that he drew all the posters, not Rick. Robert quickly leaves the premises, unsure what to think now.
Robert soon after goes to visit Darlene's sister Linda, who is in prison. Robert asks her about a "painting party" that he heard of, where there was a man who was making Darlene feel uneasy. Robert is convinced this was Rick Marshall, but Linda claims it was not a person named Rick...it was some man named "Lee."
Robert is convinced that this is Arthur Leigh Allen, and quickly rushes to Toschi's place in the middle of the night to tell him, and the former homicide detective finally relents for a meeting.
The two go to a diner, where Robert points out a number of things that could link Arthur to the Zodiac, but Toschi claims all he has is circumstantial evidence. Some even suspected that the Zodiac was someone Darlene may have known, and Arthur lived close to her place of business. Though Toschi claims he can't prove any of what Robert has revealed, he encourages him to finish his book on the Zodiac.
The time then cuts to December of 1983. Robert walks into a hardware store in Vallejo and finds himself face-to-face with Arthur Leigh Allen. No words are exchanged, before Graysmith exits the store.
Eight years later, in 1991, Mike Mageau meets with authorities, and is shown a number of mugshots. When he is questioned on which of the men could most likely be the Zodiac, he points out Arthur Leigh Allen.
In the closing credits, we are given the following information: