Clarke played the role of Elizabeth, Henry Frankenstein's fiancée, who is attacked by the Monster (Boris Karloff) on her wedding day.

The Public Enemy, released that same year, contained one of cinema's more famous (and frequently parodied) scenes, in which James Cagney pushes a half grapefruit into Clarke's face, then goes out to pick up Jean Harlow.

[7] The film was so popular that it ran 24 hours per day at a movie theatre in Times Square upon its initial release; four months after the premiere, The Hollywood Reporter informed readers that Clarke's ex-husband Lew Brice claimed to have seen the film more than 20 times (and at least twice per week) and that Brice "says he goes to see the scene wherein Mae Clarke gets hit in the eye with a grapefruit—and that it's a plazure!

[3] Clarke also appeared in the modest pre-Code Universal film Night World (1932), with Lew Ayres, Boris Karloff, Hedda Hopper, and George Raft.

In 1933, she was the female lead in Fast Workers, John Gilbert's last film as a contracted MGM star, and Lady Killer with James Cagney and Margaret Lindsay.

In the 1950s and 1960s, Clarke played uncredited bit parts in several notable films, including Singin' in the Rain, The Great Caruso, and Thoroughly Modern Millie.