MacBride launched his career as a chorister at St Thomas Fifth Avenue and then at Garden City Cathedral in New York.

[2] Beginning in 1930, like many New York-based, stage-trained actors, he found work at the Paramount, Vitaphone, and Educational studios, all of which had East Coast branches.

RKO Radio Pictures bought the film rights to Room Service as a vehicle for The Marx Brothers, and brought many of the Broadway cast members to Hollywood, including Donald MacBride reprising his role (with his catchphrase sanitized to "Jumping butterballs!").

Hollywood producers noticed MacBride's comic timing and he was established overnight as a skilled character actor.

He often played police inspectors, detectives, military officers, and other authority figures, all of whom were tormented by the leading players in the films.