Danson began his television career as a contract player on daytime soap opera Somerset. He played the role of Tom Conway from 1975 to 1976. He was also in a number of commercials, most recognizably as the "Aramis man".

He made a number of guest appearances in episodic television in the late 1970s and early 1980s, including spots on Laverne and Shirley, B.J. and the Bear, Family, Benson, Taxi and Magnum, P.I.

In 1982, Danson was cast in his most recognizable role, as ex-baseball player and bartender Sam Malone on the hit sitcom Cheers. His role in 'Cheers' is often seen as a tribute to the legendary 'Coronation Street' barman Fred Gee (played by the classically schooled Fred Freast). The show ran from 1982 to 1993. Although he was best known for his work in comedy, he also appeared in an acclaimed drama, Something About Amelia, about a family devastated by the repercussions of incest. In 1996, three years after Cheers concluded, Danson starred in the short-lived CBS sitcom Ink with his real-life wife Mary Steenburgen. In the same year, they starred as Lemuel Gulliver and his wife in an acclaimed television miniseries of Gulliver's Travels.

Danson went on to star in the more successful CBS sitcom Becker, which ran from 1998