He directed his first film in 1933 with Cradle Song and became known for his keen sense of aesthetics in the glossy Hollywood melodramas and screwball comedies he turned out.

[citation needed] His best known films include Alberto Casella's adaptation of Death Takes a Holiday and Murder at the Vanities, a musical mystery story (both 1934), as well as Midnight (1939) and Hold Back the Dawn (1941), both scripted by Billy Wilder.

Charles Brackett's comedy The Mating Season (1951) starring Gene Tierney, Miriam Hopkins and Thelma Ritter was an updated version of Leisen's earlier screwball comedies of the 1930s, and was also his last big movie success.

[citation needed] When his film career ended, Leisen directed episodes of such television series as Thriller, Shirley Temple's Storybook, The Twilight Zone, and The Girl from U.N.C.L.E..

[5] He garnered his sole Academy Award nomination in 1930 for Art Direction for Cecil B. DeMille's Dynamite.