In 1975, he landed his first television role as a cast member of the ABC variety show Saturday Night Live with Howard Cosell. That same season, another variety show titled NBC's Saturday Night premiered. Cosell's show lasted just one season.
Murray rose to prominence when he joined the cast of NBC's newly-titled Saturday Night Live the following season, replacing Chevy Chase. This was initially a turbulent experience for Murray. He often flubbed his lines and seemed awkward on camera. Chase had been the most popular cast member and some fans sent Murray hate mail stating he was a poor replacement. When Chase appeared as a guest host that season, they reportedly got into a fist fight backstage. But by the end of Murray's first season, he had begun to display his witty, laid-back persona. His characters, such as Nick the Lounge Singer and nerd Todd DiLamuca, became very popular with viewers. With the departure of Dan Aykroyd and John Belushi in 1979, Murray became the most popular member of the ensemble cast. In 1980, the entire cast left the show.
Murray later revisited the troupe he started with in the TV special Bill Murray Live From the Second City in 1980.
Murray landed his first starring role with the film Meatballs in 1979. He followed up with his portrayal of famed writer Hunter S. Thompson in 1980's Where the Buffalo Roam. In the early 1980s, he starred in a string of box-office hits including Caddyshack ("at least I got that goin' for me...), Stripes and Tootsie.
Murray began work on a film adaptation of the novel The Razor's Edge. The film, which Murray also co-wrote, was his first starring role in a dramatic film. He later agreed to star in Ghostbusters in a role originally written for John Belushi. This was a deal Murray made with Columbia Pictures in order to gain financing for his film. Ghostbusters became the highest-grossing film of 1984. But The Razor's Edge, which was filmed before Ghostbusters but not released until after, was a box-office flop. Upset over the failure of Razor's Edge, Murray took four years off from acting to study French at the Sorbonne. With the exception of a memorable cameo in the 1986 movie Little Shop of Horrors, he did not make any appearances in films.
Murray returned to films in 1988 with Scrooged and followed up with the long-awaited sequel Ghostbusters II in 1989. In 1990, Murray made his first and only attempt at directing when he co-helmed Quick Change with producer Howard Franklin. Subsequent films What About Bob? (1991) and Groundhog Day (1993) were box-office hits and critically acclaimed.
After a string of films that did not do well with audiences (besides Kingpin, in which he played a supporting role), he received much critical acclaim for Wes Anderson's Rushmore for which he won a slew of awards. Murray then experienced a resurgence in his career as a dramatic actor. After dramatic roles in Wild Things, Cradle Will Rock, and Hamlet (as Polonius), and a comedic role in Wes Anderson's The Royal Tenenbaums, he garnered considerable acclaim for the 2003 film Lost in Translation. He received a Golden Globe Award and a BAFTA award, as well as a nomination for the Academy Award for Best Actor. In an interview included on the Lost in Translation DVD, Murray states that this is his favorite movie in which he has appeared.
During this time, Murray still appeared in comedic roles such as Charlie's Angels and Osmosis Jones. In 2004, he provided the voice of Garfield in Garfield: The Movie and marked his third collaboration with Wes Anderson in The Life Aquatic with Steve Zissou. Murray also garnered acclaim for his dramatic role in Jim Jarmusch's Broken Flowers.
In 2005, he announced that he would take a break from acting, as he had not had the time since his new breakthrough in the late-1990s. His last film role to date is Garfield's voice in the sequel Garfield: A Tail of Two Kitties.