In 1927, he was retained by Horace Liveright to revise Hamilton Deane's stage adaptation of Dracula for its American production. His 1929 play Berkeley Square later formed the basis of the musical On a Clear Day You Can See Forever. His Dracula subsequently formed the basis of the 1931 film version, leading Balderston into a screenwriting career, initially for Universal Pictures horror films: in addition to Dracula, he contributed to Frankenstein, Bride of Frankenstein, The Mummy, and Dracula's Daughter. He spent much of his career adapting novels for the screen, including The Prisoner of Zenda in 1937 and 1944's Gaslight, which earned him his second Academy Award nomination (the first was for 1935's The Lives of a Bengal Lancer). He was also one of the team of writers who collaborated on the 1939 film adaptation of Gone with the Wind.
His 1932 play Red Planet was filmed as Red Planet Mars in 1952.