Finding himself broke, he began taking extra parts in 1925 and then bit parts in as many films as he could, including Texas Cyclone and Two Fisted Law with another newcomer to Hollywood, John Wayne. Brennan also had bit parts in The Invisible Man (1933), Girl Missing (1933), the Three Stooges short Woman Haters (1934), and Bride of Frankenstein (1935), in which he enjoyed a brief speaking part, and also worked as a stunt man. In the 1930s, he began appearing in higher-quality films and received more substantial roles as his talent was recognized. This culminated with his receiving the first Academy Award for Best Supporting Actor for his role as Swan Bostrom in the period film Come and Get It (1936). Two years later, he portrayed town drunk and accused murderer Muff Potter in The Adventures of Tom Sawyer. 　　Throughout his career, Brennan was frequently called upon to play characters considerably older than he was in real life. The loss of many teeth in a 1932 accident, rapidly thinning hair, thin build, and unusual vocal intonations all made him seem older than he really was. He used these features to great effect. In many of his film roles, Brennan wore dentures; in Northwest Passage – a film set in the late-18th century – he wore a special dental prosthesis which made him appear to have rotting and broken teeth. 　　For director Jean Renoir's first American film, Brennan played the top-billed lead in Swamp Water (1941), a drama also featuring Walter Huston and starring Dana Andrews. 　　In Sergeant York (also 1941), he played a sympathetic preacher and dry-goods store owner who advised the title character, played by Gary Cooper. Brennan and Cooper appeared in six films together. In 1942, he played reporter Sam Blake, who befriended and encouraged Lou Gehrig (also played by Cooper) in Pride of the Yankees. He was particularly skilled in playing the sidekick to the protagonist or as the "grumpy old man" in films such as To Have and Have Not (1944), the Humphrey Bogart vehicle which introduced Lauren Bacall. Though he was hardly ever cast as the villain, notable exceptions were his roles as Judge Roy Bean in The Westerner (1940) with Gary Cooper, for which he won his third best supporting actor Academy Award, 'Old Man' Clanton in My Darling Clementine (1946) opposite Henry Fonda, and the murderous Colonel Jeb Hawkins in the James Stewart episode of the Cinerama production, How the West Was Won (1962). 　　From 1957–1963, he starred in the ABC television series The Real McCoys, a situation comedy about a poor West Virginia family that relocated to a farm in Southern California. After five years on ABC, The Real McCoys switched to CBS for a final season. Brennan joined with the series creator, Irving Pincus, to form Brennan-Westgate Productions. The series was co-produced with Danny Thomas's Marterto Productions, and also featured Richard Crenna, Kathleen Nolan, Lydia Reed, and Michael Winkelman. 　　Brennan appeared in several other movies and television programs, usually as an eccentric "old timer" or "prospector". Prior to the launching of The Real McCoys, Brennan appeared as himself as a musical judge in the 1953-1954 ABC series Jukebox Jury. On May 30, 1957, he guest starred on NBC's The Ford Show, Starring Tennessee Ernie Ford.[5] He also made a few recordings, the most popular being "Old Rivers" about an eccentric but much-beloved farmer; it was released as a single in 1962 by Liberty Records with "The Epic Ride Of John H. Glenn" on the flip side, and peaked at number five in the U.S. Billboard charts. In his music, Brennan sometimes worked with Allen "Puddler" Harris, a Louisiana native who was a member of the original Ricky Nelson Band. He appeared as an extremely cantankerous sidekick with John Wayne and Dean Martin in Howard Hawks' 1959 western Rio Bravo and also co-starred with James Garner a decade later in Support Your Local Sheriff!, playing the ruthless head of the villainous Danby family. 　　Brennan starred as wealthy executive Walter Andrews, derived from his real name, in the short-lived 1964–1965 ABC series The Tycoon, with Van Williams. In 1967, he starred in another ABC series, The Guns of Will Sonnett, as an older man in search of his gunfighter son, James Sonnett, with his grandson, Jeff, played by Dack Rambo. After the series went off the air in 1969, Brennan continued working in both television and feature films. He received top billing over Pat O'Brien in the TV movie The Over-the-Hill Gang (1969) and Fred Astaire in The Over-the-Hill Gang Rides Again the following year. From 1970 to 1971, he was a regular on the CBS sitcom To Rome with Love, with John Forsythe. This was Brennan's last television program as a member of the permanent cast.