Meyer first gained public attention for his best-selling 1974 Sherlock Holmes novel The Seven-Per-Cent Solution, a story of Holmes confronting his cocaine addiction with the help of Sigmund Freud.

The Seven-Per-Cent Solution was later adapted as a 1976 film of the same name, for which Meyer wrote the screenplay. The film was directed by Herbert Ross and starred Nicol Williamson, Robert Duvall, Alan Arkin and Laurence Olivier. For his work adapting the novel, Meyer was nominated for an Academy Award for Best Adapted Screenplay at the 49th Academy Awards.

Time After Time (1979) starred Malcolm McDowell, Mary Steenburgen and David Warner. It was a critical and commercial success.

Meyer later directed the 1983 television film The Day After, starring Jason Robards, JoBeth Williams, John Cullum, Bibi Besch, John Lithgow and Steve Guttenberg, which depicted the ramifications of a nuclear attack on the United States. Meyer had originally decided not to do any television work, but changed his mind upon reading the script by Edward Hume. For his work on The Day After, Meyer was nominated for an Emmy Award for Best Director. Afterward, he also directed "The Pied Piper of Hamelin", a 1985 episode of the television series Shelley Duvall's Faerie Tale Theatre.

He resumed directing theatrical films with the 1985 comedy Volunteers, starring Tom Hanks and John Candy. After directing Volunteers, Meyer returned to working on Star Trek, co-writing the screenplay for Star Trek IV: The Voyage Home (1986) with Producer Harve Bennett.

Although he "refuse[d] to specialize" and so vowed to not work on another Star Trek project, Meyer co-wrote the screenplay for the fourth Star Trek film, Star Trek IV: The Voyage Home with Bennett. For that film, Bennett wrote the first and third acts, which occur in the 23rd century, and Meyer wrote the second act, which occurs in 1986 San Francisco. Meyer has said that one of the most enjoyable aspects of working on this film was getting the chance to re-use elements which he had been forced to discard from his earlier film, Time After Time. Star Trek IV proved to be successful financially, notable for succeeding with general moviegoers as well as science fiction and Star Trek devotees.

Meyer's next directing job was the 1988 Merchant Ivory produced drama The Deceivers, with Pierce Brosnan as British officer william Savage. Meyer later wrote and directed the 1991 spy comedy Company Business, starring Gene Hackman and Mikhail Baryshnikov as aging American and Russian secret agents. In 1991, Meyer once again returned to the world of Star Trek, co-writing and directing Star Trek VI: The Undiscovered Country, which became a swan song for the original cast. Meyer performed uncredited rewrites on an early draft of the screenplay of the 1997 James Bond film Tomorrow Never Dies.

Meyer worked for the Star Trek franchise again for the sixth film in the series, Star Trek VI: The Undiscovered Country (1991). He developed the story with Leonard Nimoy and co-wrote the screenplay with long-time friend and assistant Denny Flinn. He directed the picture, which was the final film to feature the entire classic Star Trek cast. Like its predecessors, this film was successful financially, grossing $74 million in the domestic market. Many of Meyer's personal papers from his involvement with the Star Trek franchise are housed at the University of Iowa Libraries.

Meyer adapted the Philip Roth novel The Human Stain into the 2003 film of the same name. In 2006, he teamed with Martin Scorsese to write the screenplay for Scorsese's adaptation of Edmund Morris's Pulitzer Prize winning biography of Theodore Roosevelt, The Rise of Theodore Roosevelt. The story traces Roosevelt's early life.

The two part, four hour, History Channel event miniseries, Houdini, starring Adrien Brody, aired over Labor Day 2014. Meyer’s script was nominated for a WGA award and the series was nominated for seven Emmys.

In February 2016 it was announced that Meyer would be returning to Star Trek by joining the writing team for CBS's new TV series Star Trek: Discovery.