Despite his lasting association with the world of horror, Price started out as a character actor. He made his film debut in 1938 with Service de Luxe and established himself in the film Laura (1944), opposite Gene Tierney, directed by Otto Preminger. He also played Joseph Smith in the movie Brigham Young (1940) and William Gibbs McAdoo in Wilson (1944) as well as a pretentious priest in The Keys of the Kingdom (1944).
Price's first venture into the horror genre was in the 1939 Boris Karloff film Tower of London. The following year he portrayed the title character in the film The Invisible Man Returns (a role he reprised in a vocal cameo at the end of the 1948 horror-comedy spoof Abbott and Costello Meet Frankenstein).
In 1946, Price reunited with Tierney in two notable films, Dragonwyck and Leave Her to Heaven. There were also many villainous roles in film noir thrillers likeThe Web (1947), The Long Night (1947), Rogues' Regiment (1948), and The Bribe (1949) with Robert Taylor, Ava Gardner, and Charles Laughton. Price's first starring role was as conman James Addison Reavis in the 1950 biopic The Baron of Arizona. He also did a comedic turn as the tycoon Burnbridge Waters, co-starring with Ronald Colman in Champagne for Caesar, one of his favourite film roles. He was active in radio, portraying the Robin Hood-inspired crime-fighter Simon Templar in The Saint, which ran from 1943 to 1951.
In the 1950s, Price moved into horror films, with a role in House of Wax (1953), the first 3-D film to land in the year's top ten at the North American box office. His next roles were The Mad Magician (1954), the monster movie The Fly (1958) and its sequel Return of the Fly (1959). Price starred in the original House on Haunted Hill (1959) as the eccentric millionaire Fredrick Loren. He played Dr. Warren Chapin, in The Tingler, a 1959 horror-thriller film by the American producer and director William Castle. Price also appeared to great effect in the radio drama "Three Skeleton Key," the story of an island lighthouse besieged by an army of rats. He first performed the work in 1950 on Escape and returned to it in 1956 and 1958 for Suspense.
Outside of the horror realm, Price played Baka (the master builder) in The Ten Commandments. About this time he also appeared on NBC's The Martha Raye Show.In the 1955–1956 television season, he was cast three times on the religion anthology series Crossroads, a study of clergymen from different denominations. In the 1955 episode "Cleanup," Price portrayed the Reverend Robert Russell. In 1956, he was cast as Rabbi Gershom Mendes Seixas in "The Rebel" and as the Reverend Alfred W. Price in "God's Healing."