Chandler maintained a successful career throughout the 1920s as a Dancer and Comedian in vaudeville and burlesque, at times teamed with Naomi Morton, granddaughter of vaudeville and Broadway star Sam Morton.

In 1930, Chandler, still billed as Fehmer Chandler, joined the cast of the Liberty Bell Filling Station radio show starring Chic Sale, as Rodney Gordon, the assistant to Wheel Wilkins (Sale), proprietor of the titular gas station. Two years later, he landed a role in the Ben Hecht-Gene Fowler Broadway play The Great Magoo. Spotting him there, film Producer David O. Selznick signed Chandler, now billed under his boyhood nickname Chick, to a film contract at RKO, telling the press that Chandler was "a cross between Lee Tracy and James Cagney." Chandler, who had done behind-the-camera work for Director Charles Brabin in 1923 and had appeared in at least one silent film as an actor, turned full-time to movie acting with his first films under contract, Sweepings and Melody Cruise, in 1933. He appeared mainly in supporting roles, mostly comic, in nearly 120 films over the next 36 years.

Chandler was engaged to Ziegfeld Follies performer and Christy model Dorothy Knapp, whom he had met while visiting his brother at West Point Military Academy in 1925. Knapp broke off the engagement to pursue her career further, and Chandler then became partnered, both privately and professionally, with 17-year-old Sallie Sharon, whom he also met at West Point. The pair formed a vaudeville team, but never married. On April 4, 1931, Chandler married Eugenia "Jean" Frontai, a former contract performer with David Belasco's theatrical company. They were married 57 years, until Chandler's death from a heart attack on September 30, 1988. (Jean Chandler followed her husband in death [from cancer] the next day in the same hospital, South Coast Medical Center.) The couple had no children.

In 1955, Chandler was cast in the starring role of Toubo Smith in the adventure series Soldiers of Fortune alongside John Russell as Tim Kelly. In the show, Smith and Kelly traveled the world engaging in treasure hunts, rescues, and exploration adventures. It brought Chandler his greatest fame. During the off-seasons, he toured the country in stock and musical theatrical productions such as Harvey and Annie Get Your Gun.

He was also a regular on the short-lived 1961 NBC comedy series One Happy Family. In the 1959 debut episode of NBC's Johnny Staccato, he played a police detective who was friends with John Cassavetes' title character. He also portrayed Photographer "Billy Hackett" in the I Love Lucy episode "Ethel's Hometown". In 1965 he played the old Fisherman Andy McGrew in the Lassie episode "Trouble at Paradise Lake" (Season 12, Ep. 7). He retired in 1971 following a sixth guest appearance on Bonanza.