Meredith was born in Cleveland, Ohio.  He was the youngest of three children of William George Meredith--a physician--and Ida Beth Burgess. In the late 1920s, Meredith drifted to New York, where he had numerous jobs including selling vacuum cleaners, clerking at Macy's, and working as a runner on Wall Street. He then made two trips to South America as an ordinary seaman on an ocean liner, after which he was fired for disobeying orders.  Meredith attended Cathedral Choir School, Cleveland; Hoosac Falls Preparatory School, New York; Amherst College, Massachusetts.

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 and as war correspondent Ernie Pyle in The Story of G.I. Joe (1945). He was featured in many 1940s films, including three (Second Chorus (1940), Diary of a Chambermaid (1946) and On Our Merry Way (1948) ) co-starring then-wife Paulette Goddard. 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. [citation needed] 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.

Meredith served in the United States Army Air Forces in World War II, reaching the rank of captain. He transferred to the Office of War Information and was involved in making films for G.I.s..  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.

Burgess Meredith was adept playing both dramatic and comedic roles, and appeared in four different starring roles in the acclaimed anthology TV series The Twilight Zone (only Jack Klugman had as many leading guest appearances). 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. In the 1961 episode "Mr. Dingle, the Strong", Meredith plays the title character, a timid weakling who, as the subject of a space alien's experiment on human nature, suddenly acquires superhuman strength. In "Printer's Devil," Meredith portrayed the Devil himself, and in "The Obsolete Man" he portrayed a deeply religious man, sentenced to death in a future, dystopic totalitarian society.

Meredith achieved iconic status for playing The Penguin in the television series Batman.

In 1972 - 1973, Meredith played V.C.R. Cameron, director of "Probe Control," in the movie "Probe" and then in "Search," the subsequent TV series (the name was changed to avoid conflict with a program on PBS). The series involved "World Securities Corporation," a private agency which, among other activities, fielded a number of detectives equipped with high-tech equipment including a tiny TV transmitter (the "Scanner") which allowed Probe Control to see what was going on where the agents were working. One episode centered around Cameron being kidnapped and having to escape from a torture chamber, without any of the tools carried by Probe agents.

Meredith was a favorite of director Otto Preminger, who cast him in Advise and Consent (1962), In Harm's Way (1965), Hurry Sundown (1967), Skidoo (1968) and Such Good Friends (1971). He appeared in Ray Harryhausen's last stop-motion feature Clash of the Titans, in a supporting role. He also played Rocky Balboa's trainer, Mickey, in the first three Rocky films (1976), (1979) and (1982), to great acclaim. His character Mickey died in the third Rocky film but returned briefly for the fifth film Rocky V (1990) in flashbacks. Meredith also appeared 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). He was the Penguin in the original Batman Movie. As a nod to his longtime association with The Twilight Zone, he served as narrator for the 1983 film based on the series. He was Academy Award-nominated in the Best Supporting Actor category for his roles in The Day of the Locust (1975) and Rocky (1976).

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

Meredith also did 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 adaptation of the Peter, Paul, and Mary song Puff, The Magic Dragon.

For his contribution to the motion picture industry, Meredith has a star on the Hollywood Walk of Fame at 6904 Hollywood Blvd.  Critic Wolcott Gibbs once hailed Meredith in The New Yorker as "brilliant, impressive, heartbreaking, vibrant and eloquent."  Gibbs was, of course, talking of Meredith the stage performer. Sadly, there are only a handful of film roles that live up to that estimation.

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

Meredith died of Alzheimer's disease and melanoma in 1997.