After his military service he moved to New York, where he made his Broadway debut at Threepenny Opera in 1955. In Chicago, too, he occasionally played sketch comedy with what is now Second City. Two years later, he made his onscreen debut on the TV series Studio One and played continuously on television for most of his career.

His breakthrough role came in 1970 when he made his debut as Lou Grant on the sitcom The Mary Tyler Moore Show, which became a huge hit and earned him three Emmys. The show starred Mary Tyler Moore, who died in 2017 at the age of 80, and Betty White, 99.

Asner repeated his role in the spin-off series Lou Grant in 1977 and won two more Emmys for his part. He also won Emmys for roles in Rich Man, Poor Man and the miniseries Roots.

Asner has also done a lot of voice acting during his career. In the 90s he was part of the cast of Batman: The Animated Series, Gargoyles, Spider-Man: The Animated Adventures, Freakazoid! and Captain Planet and the Planeteers, in which he portrayed the villain Hoggish Greedly.