Boris Karloff arrived in Hollywood and he made dozens of silent films, but work was sporadic, and he often had to take up manual labor, such as digging ditches and driving a cement truck, to pay the bills. His role as Frankenstein's monster in Frankenstein (1931) made him a star. A year later, he played another iconic character, Imhotep, in The Mummy.

The five-foot, eleven-inch, brown-eyed Karloff played a wide variety of roles in other genres besides horror. He was memorably gunned down in a bowling alley in the 1932 film Scarface. He played a religious WWI soldier in the 1934 John Ford epic The Lost Patrol. Karloff gave a string of lauded performances in 1930s Universal horror movies, including several with his main rival as heir to the horror throne of Lon Chaney, Sr.: Béla Lugosi, whose refusal to play the monster in Frankenstein made Karloff's subsequent career possible. Karloff played Frankenstein's monster three times; the other films being Bride of Frankenstein (1935) and Son of Frankenstein (1939), which also featured Lugosi as the demented Igor, spelled "Ygor" in this movie. Karloff would revisit the Frankenstein mythos in film several times after leaving the role. The first would be as the villainous Dr. Niemann in House of Frankenstein (1944), where Karloff would be famously contrasted against the then more popularized Glenn Strange, who became the standardized interpretation of the Monster during the 1940s, 1950s, and 1960s.

Karloff returned to the role of the "mad scientist" in 1958's Frankenstein 1970, as Baron Victor von Frankenstein II, the grandson of the original inventor. The final twist reveals the crippled Baron has given his own face (i.e., "Karloff's") to the Monster. The actor appeared at a celebrity baseball game as the Monster in 1940, hitting a gag home run and making catcher Buster Keaton fall into an acrobatic dead faint as the Monster stomped into home plate. Norman Z. McLeod filmed a sequence in The Secret Life of Walter Mitty with Karloff in the Monster make-up, but it was deleted. Karloff donned the headpiece and neck bolts for the final time in 1962 for a Halloween episode of the TV series Route 66, but he was playing "Boris Karloff," who, within the story, was playing "the Monster."

While the long, creative partnership between Karloff and Lugosi never led to a close mutual friendship, it produced some of each actor's most revered and enduring productions, beginning with The Black Cat. Follow-ups included Gift of Gab (1934), The Raven (1935), The Invisible Ray (1936), Black Friday (1940), You'll Find Out (also 1940), and The Body Snatcher (1945). During this period he also starred with Basil Rathbone in Tower of London (1939).

During this period, Karloff was also a frequent guest on radio programs, whether it was starring in Arch Oboler's Chicago-based Lights OutFred Allen or Jack Benny. productions, most notably the episode "Cat Wife," or spoofing his horror image with

An enthusiastic performer, he returned to the Broadway stage in the original production of Arsenic and Old Lace in 1941, in which he played a homicidal gangster enraged to be frequently mistaken for Karloff. Although Frank Capra cast Raymond Massey in the 1944 film, (which was shot in 1941, while Karloff was still appearing in the role on Broadway), Karloff reprised the role on television with Tony Randall and Tom Bosley in a 1962 production on the Hallmark Hall of Fame. Somewhat less successful was his work in the J. B. Priestley play The Linden Tree. He also appeared as Captain Hook in the play Peter Pan with Jean Arthur. He was nominated for a Tony Award for his work opposite Julie Harris in The Lark, by the FrenchJean Anouilh about Joan of Arc, which was also reprised on Hallmark Hall of Fame. playwright

In later years, Karloff hosted and acted in a number of television series, most notably Thriller, Out of This World, and The Veil, the latter of which was never broadcast and only came to light in the 1990s. In the 1960s, Karloff appeared in several films for American International Pictures, including Comedy of Terrors, The Raven, and The Terror, the latter two directed by Roger Corman.

During the 1950s Karloff appeared on British TV in the series Colonel March of Scotland Yard, in which he portrayed John Dickson Carr's fictional detective Colonel March who was known for solving apparently impossible crimes.

As a guest on The Gisele MacKenzie Show, Karloff sings "Those Were the Good Old Days" from Damn Yankees, while Gisele MacKenzie performs the solo, "Give Me the Simple Life". On The Red Skelton Show, Karloff guest starred along with horror actor Vincent Price in a parody of Frankenstein, with Red Skelton as the monster "Klem Kadiddle Monster." In 1966 Karloff also appeared with Robert Vaughn and Stefanie Powers in the spy series The Girl from U.N.C.L.E., in the episode "The Mother Muffin Affair." Karloff performed in drag as the titular Mother Muffin. That same year he also played an Indian Maharajah on the adventure series The Wild Wild West ("The Night of the Golden Cobra"). In 1967, he played an eccentric Spanish professor who thinks he's Don Quixote in a whimsical episode of I Spy ("Mainly on the Plains").

In the mid-1960s, Karloff gained a late-career surge of American popularity when he narrated the made-for-television animated film of Dr. Seuss' How the Grinch Stole Christmas, and provided "the sounds of the Grinch" (the song "You're a Mean One, Mr. Grinch" was sung not by Karloff, but by American voice actor Thurl Ravenscroft). Karloff later won a Grammy in the spoken word category after the story was released as a record.

In 1968 he starred in Targets, a movie directed by Peter Bogdanovich about a young man who embarks on a spree of killings carried out with handguns and high powered rifles. The movie starred Karloff as "retired horror film actor" Byron Orlok (a lightly-disguised version of himself) facing an end of life crisis, resolved through a confrontation with the shooter.

Karloff ended his career appearing in a trio of low-budgeted Mexican horror films that were shot shortly before his death; all were released posthumously, with the last, The Incredible Invasion, not seeing release until 1971, two years after Karloff's death.