After serving briefly in the United States Navy near the end of World War II, Douglas became a vocalist in the big band of Kay Kyser, with whom he was featured on two notable hits, "Ole Buttermilk Sky" in 1946 and "The Old Lamplighter" the following year. He remained part of Kyser's band until Kyser retired from show business in 1951.

He next surfaced in 1961 in Cleveland, where he was hired for $400 a week as an afternoon television talk-show host at KYW-TV. The show rapidly gained popularity, and ultimately, national syndication in August 1963 on five Westinghouse-owned stations. It stopped broadcasting live in 1965 after guest Zsa Zsa Gabor used inappropriate language on the air. The program moved to Philadelphia in June of 1965. Guests ranged from Truman Capote and Richard M. Nixon to The Rolling Stones and Herman's Hermits. The show helped introduce entertainers such as Barbra Streisand and Aretha Franklin. Regrettably, Streisand's appearance, like many others of this era, was discarded by KYW-TV.

After the move to Philadelphia, Douglas also attempted to revive his own singing career, logging his lone Top 40 single as a solo artist, "The Men In My Little Girl's Life," in 1966.

By 1967 The Mike Douglas Show was broadcasting to 171 markets and 6,000,000 viewers each day, mostly women at home. It earned $10.5 million from advertisers, while its host was paid more than $500,000. In 1967, the program received the first Emmy Award for Individual Achievement in Daytime Television from the National Academy of Television Arts and Sciences.

Douglas became a local cultural icon in Philadelphia, often inviting prominent players from the city's professional sports teams to be guests on his show (he had a particular affinity for the city's pro football team, the Philadelphia Eagles, constantly referring to the team as "Our Eagles," and he could often be seen in attendance at Eagles' home games, especially whenever they appeared on Monday Night Football). He also assisted in mayor Frank Rizzo's campaign against derisive jokes often told by outsiders about the city, acting as chief spokesperson for the "Anti-Defamation Agency" Rizzo had set up for this purpose.

In July of 1978, the talk show's home base was transferred to Los Angeles, where it remained until finally going off the air in 1981. A second series, "The Mike Douglas Entertainment Hour," ended production in 1982.