In the '40s, Dean Martin teamed up with Jerry Lewis, a comedian he met in a New York club, and started performing music and comedy acts together. Their official debut was in 1946 in a club in Atlantic City. Their initial performance was not well received and the club manager threatened he would fire them if they didn't come up with something better by the end of the night. So they threw away their scripts and improvised, this time causing the audience to double over in laughter. The secret of this success as they said was that they forgot about the audience and just played.

In 1949, Martin and Lewis started a radio series together and also signed a contract with Hal Wallis, a Paramaount producer. They did several films together and were a huge success, mainly due to their friendship on and off-stage, which took their performance to a whole new level. However, as Dean Martin did mostly the singing and he hadn't yet developed his style, critics prayed Lewis as the main contributor to the show and claimed that he could succeed with anyone. This ultimately caused their relationship to brake and Martin continued with his solo career. He was hired to play as a co-star in The Young Lions in 1957 but later the producers decided to give him the whole part. The movie was a big success and was the beginning of the artist's comeback. Later on he played in Some Came Running together with Frank Sinatra. The movie was another big hit. Martin's performance playing the part of Dude in the movie Rio Bravo released in 1959 was also much appraised by critics. By mid '65, he had already established himself as a top movie star, while Jerry Lewis' career was declining.

Dean Martin also played a satiric illustration of his own personality in the adult comedy directed by Billy Wider Kiss Me, Stupid (1964) and teamed up with John Wayne in The Sons of Katie Elder, in 1965. The image of the two as brothers was somewhat unconvincing. During the '60s, he played in a series of Matt Helm, which he co-produced.