After playing in college shows, repertory theatre, and vaudeville, he became a major radio star in the early 1930s, which led to the offer of a movie contract from 20th Century Fox in 1935.

Returning to film work in his later years, Ameche enjoyed a fruitful revival of his career, beginning with his role as a villain in Trading Places (1983).

He enjoyed the experience and got a juvenile lead in Jerry For Short in New York, followed by a tour in vaudeville with Texas Guinan until she dropped him from the act, dismissing him as "too stiff".

By 1932, Ameche had become the leading man on two other Chicago-based programs: the dramatic anthology First Nighter, and Betty and Bob, the latter considered by many to be the forerunner of the soap-opera genre.

"[4] Brought to Hollywood by 20th-Century Fox producer Darryl Zanuck, Ameche played mostly romantic leads paired with many of the top female stars of the era.

As noted by Mike Kilen in the Iowa City Gazette (December 8, 1993), "The film prompted a generation to call people to the telephone with the phrase: 'You're wanted on the Ameche.

Ameche was Alice Faye's leading man in Hollywood Cavalcade (1939), then played another real-life figure, Stephen Foster, in Swanee River (1939).

Following his appearances as announcer and sketch participant on The Chase and Sanborn Hour, Ameche achieved memorable success during the late 1940s playing opposite Frances Langford in The Bickersons, the Philip Rapp radio comedy series about a combative married couple.

[15] After having to track him down in Santa Monica, California due to not being able to reach him through the Screen Actors Guild, who said that his royalty payments were going to his son in Arizona, Ameche took on the role.

He earned good reviews for the David Mamet and Shel Silverstein-penned Things Change (1988); The New York Times said that he showed "the kind of great comic aplomb that wins actors awards for other than sentimental reasons.