Ameche's first big film was the Technicolor adventure romance, "Ramona" (1936), which cast him (rather oddly, in retrospect) as a Native American opposite Loretta Young. Over the course of the next fifteen years, he would serenade Sonja Henie in her first skating fest ("One in a Million" 1936), romance Joan Bennett in a bomb shelter ("Confirm or Deny" 1941) and threaten Claudette Colbert's life ("Sleep My Love" 1948). His very pleasant singing voice made him a suitable partner for Betty Grable in "Moon Over Miami" (1941), though the Fox musical blonde he was most often paired with was honey-voiced Alice Faye, with whom he made six films. Two of their best were lavish historical sagas: the famous one about the Chicago fire, "In Old Chicago" (1938), with Ameche as the upstanding son contrasted with engaging bad boy Tyrone Power; and the biopic of legendary entertainer "Lillian Russell" (1940). He and Faye also paired for the affectionate recreation of early Hollywood slapstick "Hollywood Cavalcade" (1939), with Ameche playing a thinly disguised rendition of Mack Sennett.

Although Ameche's typecasting in light fare hampered him somewhat when it came to achieving front-rank stardom, critical plaudits or plum roles, two of his finest films were comedy masterpieces with no apologies necessary. Mitchell Leisen's "Midnight" (1939), with Colbert and a stunning cast making the most of an acid Charles Brackett-Billy Wilder script, perfectly summed up Paramount's sophisticated sparkle and, indeed, much of 30s romantic comedy. Ernst Lubitsch's warm and witty period piece, "Heaven Can Wait" (1943), meanwhile, offered Ameche the role of a lifetime as a likable rogue relating his past peccadilloes to the Devil at the entrance to Hell.

His stardom faded late in the 40s after he and Fox parted company, but Ameche kept extremely busy in variety programs on TV through the 50s, often teaming with his 30s radio co-star singer Frances Langford. Beginning in 1961, Ameche's bravado and panache served him well in his best-remembered TV role, that of ringmaster of "International Showtime" (NBC, 1961-65), traveling worldwide to present different circuses and magic acts each week. Throughout the 50s and 60s, the actor also returned to the musical comedy stage, appearing in such Broadway shows as Cole Porter's "Silk Stockings" (1955), and also "Goldilocks" (1958) and "13 Daughters" (1961).

The 70s found Ameche busiest in TV work, but he enjoyed renewed popularity in comedy supporting roles in 80s films beginning with "Trading Places" (1983), in which he and Ralph Bellamy were rich brothers who orchestrate the role switch between yuppie Dan Aykroyd and con man Eddie Murphy. Ameche, vibrant as ever, consolidated his success with an ideally cast, Oscar-winning turn as a man rejuvenated by a magical pool in Ron Howard's "Cocoon" (1985), including a break-dancing sequence (done mostly by a dance double). He also gave a splendid performance in his most substantial acting role of his later years as a cobbler who agrees to take a murder rap in David Mamet's "Things Change" (1988). He and co-star Joe Mantegna shared the Best Actor prize at the Venice Film Festival. The following year, he returned to Broadway, assuming the role of the Stage Manager in an affecting revival of Thornton Wilder's "Our Town". Ameche went on to play Tom Selleck's senile father in "Folks" (1992) and finished his career in a very likable turn as Ray Liotta's father in "Corinna, Corinna" (1994), completed just weeks before his death from prostate cancer. While he barely uttered a line and appeared weak and frail, Ameche used his eyes and facial expressions which spoke volumes, recalling the great silent screen performers.