While Moran was serving in the U.S. Navy in 1908, he knocked out fighter Fred Cooley in the second round. He began his career as a prize-fighter that same year with a match against Fred Broad. Soon, Moran, who had a hard right hand punch which he called "Mary Ann", became known as the "White Hope" of the teens. In 1914 he fought Jack Johnson for the Heavyweight Championship of the World, and in 1916 "The Fighting Dentist" went up against Jess Willard for the same title, but lost both bouts. He lost his last fight to Marcel Nilles for the Heavyweight Championship of France on December 22, 1922. He retired from boxing after 66 bouts with a record of 36 wins (28 by a knockout), 13 losses, 16 draws and 1 no contest.

Gravel-voiced, granite-faced former heavyweight boxer Frank C. Moran made his film debut as a convict in Mae West's She Done Him Wrong (1933). Though quickly typecast as a thick-eared brute, Moran was in real life a gentle soul, fond of poetry and fine art. Perhaps it was this aspect of his personality that attracted Moran to eccentric producer/director/writer Preston Sturges, who cast the big lug in all of his productions of the 1940s.