Whale started his professional life as a newspaper cartoonist before turning to acting during his time as a prisoner in World War I. From acting, he turned to set design and then to directing, and went to Hollywood in 1930 for the screen version of his stage hit Journey's End.

He served as a dialogue director on the World War I aerial drama Hell's Angels, but it was as a director of horror movies at Universal that Whale made his mark, with Frankenstein (1931), The Old Dark House (1932), The Invisible Man (1933), and The Bride of Frankenstein (1935). Apart from Frankenstein, which was a wholly serious horror film, these movies freely mixed chills and black comedy, and caused nearly as much laughter as shock to audiences, who devoured the potent mixture of horror and humor.

His graceful adaptation of Show Boat (1936) was one of the finest screen musicals of the 1930s, but a change in management at the studio, coupled with Whale's unhappiness at the recutting of his drama The Road Back (1937), led to his exit from Universal.

He directed other films after leaving Universal, including The Man In the Iron Mask (1939), but nothing that he did after Show Boat had any of the flair of his earlier movies, and Whale's career declined during the late 1930s.

In the early 1940s he renounced filmmaking and retired to hedonistic life of painting and all-male parties. Along the way he suffered several strokes.

He died in a drowning accident in his pool, under what were then widely regarded as mysterious circumstances. In fact it became know years after his death that he had committed suicide. He had left a suicide note to his long term partner, David Lewis in which he said:

"The future is just old age and illness and pain.... I must have peace and this is the only way."