Brimley did not become famous until he was older, appearing in such films as Hotel New Hampshire and John Carpenter's The Thing. He often plays gruff or stodgy old men, notably on the 1980s drama series Our House. This typecast was parodied by the satirical newspaper The Onion, with a sidebar caption reading "Shotgun Blast To Abdomen Just Pisses Wilford Brimley Off More."

Brimley is also well known for the commercials he has made, including a series of commercials he did for Quaker Oats Oatmeal. Recently, Brimley has also made a series of commercials for a diabetic testing supplies company, Liberty Medical. These commercials appear frequently during the airing of The Price Is Right, and in them Brimley politely (yet sternly) admonishes viewers to check their blood sugar and to check it often. The commercials were parodied in Stewie Griffin: The Untold Story .

He is known to Star Wars fans as Noa Briqualon in George Lucas' 1985 made for TV movie, entitled Ewoks: The Battle for Endor.

For an unknown reason, Wilford Brimley has become a cult figure among ROM hackers. ROM hacks featuring Wilford Brimley include "Wilford Brimley Battle" (hacked version of River City Ransom), "Wilford Kong" (hacked version of Donkey Kong), Wilford Island (hacked version of Adventure Island) and "Super Nazi Penis Cartel Freedom Fighters 3" (hacked version of Super Mario Bros. 3). A "Robotic Wilford Brimley" also appeared in the cartoon strip Pokey the Penguin, in the form of a black sphere.

In the Comedy Central show The Colbert Report, Wilford has been known to call Stephen Colbert very early in the morning, waking him up, having nonsensical conversations, and giving him ideas for Colbert's show.

In early 2006, Brimley became a popular Internet meme due to a series of music videos on YouTube.com that parodied his Liberty Medical commercials and his pronunciation of 'diabetes' as 'dia-beetis'.