Meredith was born in Cleveland, Ohio. In 1933 he became a member of Eva Le Gallienne's theatre company in New York. He attracted favorable attention for playing George in a 1939 adaptation of John Steinbeck's Of Mice and Men. He was featured in many 1940s films, including some starring actress Paulette Goddard, to whom he was married. Among later roles, he became known for playing The Penguin on the television series Batman. The Penguin's trademark quacking laugh was actually Meredith's attempt to cover up coughing fits, as his part required him to smoke, something he had not done in years. He admitted in an interview it sounded more like a duck than a penguin. Nevertheless, his role as the Penguin was so well-received that the show's writers always had a script featuring the Penguin ready whenever Meredith was available. He appeared on the show more times during its run than any other villain.

Burgess Meredith was adept playing both dramatic and comedic roles, and appeared in four different starring roles in the acclaimed 1950s anthology TV series The Twilight Zone; only Jack Klugman had as many. In the famous "Time Enough at Last", a 1959 episode of The Twilight Zone, Meredith plays a henpecked bank teller who only wants to be left alone with his books. When he takes a lunch break to read in the bank vault, he is saved from a nuclear war that destroys the world (only to lose his ability to read when his reading glasses break). In a 1961 episode, "Mr. Dingle, the Strong", Meredith plays a comedic role as the subject of a space alien's experiment on human nature. Mr. Dingle, a small, weak man, suddenly acquires superhuman strength. He uses it only to win bets and show off, and hilarity ensues. In addition, Meredith also played the devil in "Printer's Devil" and a doomed librarian in "The Obsolete Man."

Meredith played Rocky Balboa's trainer, Mickey, in the first three Rocky films, to great acclaim. His character Mickey died in the third Rocky film but returned for the fifth Rocky film as Mickey's ghost. Meredith also made a significant contribution to the world of Christmas films through his single-scene role as the Ancient One, oldest and wisest of the Elves of the Vendequm, in Santa Claus: The Movie (1985). In his twilight years, he played Jack Lemmon's character's father in Grumpy Old Men (1993) and its sequel, Grumpier Old Men (1995).

A somewhat more mixed (comedic/dramatic) role was his portrayal of the philosophical (yet hapless) tramp, Vladimir, in a notable production of Beckett's Waiting for Godot.

Meredith has also done voice over work mostly in the 1970's, supplying the voice over in TV commercials for Stokley Vegetables, United Airlines, and Freakies cereal; as well as supplying the narration for the 1974-1975 ABC Saturday morning series Korg: 70,000 B.C. and supplying the voice of Puff in the 1978 animated TV special adaption of the Peter, Paul, and Mary song Puff, The Magic Dragon.

Meredith served in the United States Army Air Forces in World War II, reaching the rank of Captain. As a result of the House Committee on Un-American Activities investigation into Communist influence in Hollywood, Meredith was placed on the Hollywood blacklist in the 1950s.

Meredith died of Alzheimer's disease and melanoma in 1997 at the age of 89. Coincidentally, his character died in his final movie, Grumpier Old Men.

For his contribution to the motion picture industry, Burgess Meredith has a star on the Hollywood Walk of Fame at 6904 Hollywood Blvd.

His autobiography So Far, So Good was published in 1994.