In 1977, he played Dr. Mitchell Pierson on the daytime soap opera The Doctors, having also appeared earlier in 1975 as another character, Dr. Chuck Weldon.

[14] His guest appearances on television in the late 1970s and early 1980s include being on Laverne & Shirley, B. J. and the Bear, Family, Benson, Taxi, Magnum, P.I., The Amazing Spider-Man, Tucker's Witch, and Mrs. Columbo.

In 1982, Danson was cast in the role of Sam Malone, a former local-legend baseball player and bartender, for the NBC sitcom Cheers.

After Cheers ended, Danson appeared in films such as Made in America, Getting Even with Dad, Loch Ness, and Saving Private Ryan.

In 1996, three years after Cheers concluded, Danson starred in the short-lived CBS sitcom Ink with his real-life wife Mary Steenburgen.

The role earned him an Emmy nomination for Outstanding Supporting Actor in a Drama Series, but he lost to co-star Željko Ivanek.

Danson starred in the HBO sitcom Bored to Death as George Christopher, the laconic and sometime downright infantile editor of Edition magazine.

[19] From 2016 to 2020 Danson appeared opposite Kristen Bell as the character Michael in the NBC sitcom The Good Place.

In 2024, he starred as the leading role of Charles in the Netflix comedy series, A Man on the Inside, based on the 2020 Academy Award-nominee documentary The Mole Agent.

[25] While a guest on The Arsenio Hall Show in late 1988, he met actress Whoopi Goldberg; he describes her as "a sexy, funny woman".

[27] While making Made in America in April 1992, the two became romantically involved, a pairing that was heavily featured in gossip tabloids such as the National Enquirer.

The couple also appeared on the Rock the Vote TV special in the same year;[28] they were set to star in a Paramount-produced version of Neal Barrett Jr.'s Pink Vodka Blues,[29] written by Marshall Brickman.

[citation needed] Danson received negative press attention October 8, 1993, after his appearance wearing blackface at a Friars Club comedy roast in honor of Goldberg, and for using many racist slurs.

Later, Goldberg defended the sketch, explaining that she had helped write much of the material and referred Danson to the makeup artist who painted his face as a societal critique.

Bill Breed, then curator of geology at the Museum of Northern Arizona, introduced Danson and their friend Marc Gaede to a "game" he referred to as "billboarding".

Armed with axes and saws, Breed, Gaede, and Danson destroyed over 500 outdoor advertising signs.

[36][37] Danson's interest in environmentalism continued over the years, and he began to be concerned with the state of the world's oceans.

[38] His commitment to the environment led him to host the A&E television series "Challenge of the Seas" in 1991, filming 26 one-hour episodes.

[39] In March 2011, Danson published his first book, Oceana: Our Endangered Oceans and What We Can Do To Save Them which was written with journalist Michael D'Orso.

Danson has donated over $177,000 as of June 2024 to Democratic candidates and PACs, including Kamala Harris, Joe Biden, Barack Obama, Al Gore, John Edwards, Barbara Boxer, Bill Clinton, Al Franken, John Kerry, and the Jane Fonda Climate PAC.

On October 3, 2016, he attended the opening of Hillary Clinton's new campaign office in Lancaster, Pennsylvania at the old Queen Pharmacy on King Street.