Her first notable role came in 1980 with A Small Circle of Friends, opposite Brad Davis and Karen Allen. The film about social unrest at Harvard University during the 1960s was a critical success. In 1981, she played Tala in the Ringo Starr vehicle Caveman, opposite Dennis Quaid. She was also featured in the Henry Winkler comedy Night Shift, about life working the night shift at a city morgue. She starred with Tom Cruise in the 1983 comedy film Losin' It.

In 1979, while pursuing her acting career, Long met securities broker Bruce Tyson, whom she married in October of 1981. She gave birth to her daughter, Juliana, on March 27, 1985.

Long's break came when she was cast as vain barmaid Diane Chambers in Cheers. The show was slow to capture an audience, but it eventually became one of the most popular shows on television. She was nominated for an Emmy four years in a row and for three Golden Globes for the NBC sitcom, winning one Emmy and two Golden Globes . The series was also nominated for five Emmys and Golden Globes for Best Comedy series, winning 2 Emmys, during her five year tenure on the show. Thereafter, she became a sought-after comedic talent.

In 1984 Long starred in the dramedyIrreconcilable Differences. Long was nominated for a Best Leading Actress Golden Globe for her performance.

Long then appeared in a string of comedies. These included The Money Pit, starring a young Tom Hanks, the crime caper Outrageous Fortune featuring Bette Midler and Peter Coyote, and the universally panned Hello Again, in which Long played a woman brought back to life several years after death.

Amid much controversy, Long abandoned her trademark Diane Chambers role and the Cheers series after the season wrapped in mid-1987, at the height of the series' popularity. Her first post-Cheers project was Troop Beverly Hills, where she played a housewife who starts a 'Wilderness Girl' troop as a distraction from her divorce proceedings. Despite poor reviews, the film was moderately successful.

Though Shelley Long saw critical and box office success during the 1980s, her career fell off the radar throughout the 1990s. She took several roles in unsuccessful films, including Don't Tell Her It's Me and Frozen Assets, which were box office disasters. In 1993 she returned to Cheers for its last three episodes. Long followed with a series of poorly received television films. In 1993 she starred in the short-lived sitcom Good Advice with Treat Williams and Teri Garr, but the project proved unsuccessful and was canceled after two seasons.

In 1995 she appeared in the campy big-screen remake The Brady Bunch Movie, which was a surprise hit and which breathed new life into her career as a comedienne. The following year, she reprised her role as Carol Brady in A Very Brady Sequel, which saw more modest success. She followed this with a series of unsuccessful television ventures, including the television remake of Freaky Friday and the family sitcom Kelly Kelly, which aired for just a few episodes on the WB. More recently, Shelley took a supporting role in the Richard Gere vehicle, Dr. T and the Women and returned for the critically lambasted third Brady installment, The Brady Bunch in the White House.

In 2004, after over 20 years of marriage, Bruce Tyson filed for divorce. Long was prescribed both pain pills and an analgesic patch to help deal with a back injury. On November 16, 2004, Long overdosed on prescription pain-killers and was admitted to UCLA Hospital for treatment, in what was an apparent suicide attempt.

As of 2006 Long continues to work as an actress.