From 1929, Ruggles appeared in talking pictures. His first was Gentleman of the Press in which he played a comic, alcoholic newspaper reporter. Throughout the 1930s he was teamed with comic actress Mary Boland in a string of domestic farces, notably Six of a Kind, Ruggles of Red Gap, and People Will Talk; Boland was the domineering wife and Ruggles the mild-mannered husband. Ruggles is best remembered today as the big-game hunter in Bringing Up Baby. In other films he often played the "comic relief" character in otherwise straight films. In all, he appeared in about 100 movies.
In 1949, Ruggles halted in his film career to return to the stage and to move into television. He was the headline character in the TV series The Ruggles, a family comedy in which he played a character also called Charlie Ruggles, and The World of Mr. Sweeney. He returned to the big screen in 1961, playing Charles McKendrick in The Parent Trap and Mackenzie Savage in The Pleasure of His Company. He had a recurring guest role on The Beverly Hillbillies in the mid-1960s as Lowell Redlings Farquhar, father-in-law of Milburn Drysdale (Raymond Bailey).
Ruggles also lent his voice to the "Aesop and Son" TV cartoons produced by Jay Ward and Bill Scott. Ruggles played Aesop; Daws Butler played "Junior."
Ruggles died of cancer at his Hollywood home in 1970 at the age of 84. He was interred in the Forest Lawn Memorial Park Cemetery in Glendale, California.
He has a star on the Hollywood Walk of Fame on Hollywood Boulevard.