Price was born in St. Louis, Missouri, the son of Marguerite Cobb (née Willcox) and Vincent Leonard Price, Sr., who was the president of the National Candy Company. His grandfather, Vincent Clarence Price, invented "Dr. Price's Baking Powder", the first cream of tartar baking powder, and secured the family's fortune.
Price attended St. Louis Country Day School. He was further educated at Yale in art history and fine art. He was a member of Alpha Sigma Phi Fraternity and the Courtauld Institute, London. He became interested in the theater during the 1930s, appearing professionally on stage from 1935.
He made his film debut in 1938 with Service de Luxe and established himself as a competent actor, notably in Laura (1944), opposite Gene Tierney, directed by Otto Preminger. He also played Joseph Smith, Jr. in the movie Brigham Young (1940), 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 in which his character was murdered by Karloff's. 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 Gene Tierney in two notable films, Dragonwyck and Leave Her to Heaven. There were also many villainous roles in slick film noir thrillers like The Web (1947), The Long Night (1947), Rogues' Regiment (1948) and The Bribe (1949) with Robert Taylor, Ava Gardner and Charles Laughton. He was also active in radio, portraying the Robin Hood-inspired crime-fighter Simon Templar, aka. The Saint, in a series that ran from 1943 to 1951.
In the 1950s, he 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, and then the monster movie The Fly (1958). Price also starred in the original House on Haunted Hill (1959) as the eccentric millionaire Fredrick Loren. In between these horror films, Price played Baka in The Ten Commandments.
In the 1960s, Price had a number of low-budget successes with Roger Corman and American International Pictures (AIP) including the Edgar Allan Poe adaptations House of Usher (1960), The Pit and the Pendulum (1961), Tales of Terror (1962), The Comedy of Terrors (1963) The Raven (1963), The Masque of the Red Death (1964), and The Tomb of Ligeia (1965). He also starred in The Last Man on Earth (1964), a film based on the Richard Matheson novel I Am Legend. In 1968 Price gave an iconic, coldly menacing, performance as Matthew Hopkins the "Witchfinder General" in the film of the same name.
He also starred in comedy films, notably the cult-classic Dr. Goldfoot and the Bikini Machine (1965). In 1968 he played the part of an eccentric artist in the musical Darling of the Day opposite Patricia Routledge, displaying an adequate if untrained singing voice.
He often spoke of his pleasure at playing Egghead in the Batman television series. One of his co-stars, Yvonne Craig (Batgirl), said Price was her favorite. In an often-repeated anecdote from the set of Batman, Price, after a take was printed, started throwing eggs at series stars Adam West and Burt Ward, and when asked to stop replied, "With a full artillery? Not a chance!", causing an eggfight to erupt on the soundstage. This incident is reenacted in the behind-the-scenes telefilm Return to the Batcave: The Misadventures of Adam and Burt.
It was also in the 1960s that he began his role as a guest on the game show The Hollywood Squares, even becoming a semi-regular in the 1970s, including being one of the guest panelists on the finale in 1980. He was known for usually making fun of Rose Marie's age, and using his famous voice to answer maliciously to questions.
During the early 1970s, Price hosted and starred in BBC Radio's horror and mystery series The Price of Fear. Price accepted a cameo part in the children's television program The Hilarious House of Frightenstein (1971) in Hamilton, Ontario Canada, on the local television station CHCH. In addition to the opening and closing monologues, his role in the show was to recite poems about the show's various characters, sometimes wearing a cloak or other costumes. He also appeared in The Abominable Dr. Phibes (1971) and Theatre of Blood (1973), in which he created a pair of campy serial killers. Price also recorded dramatic readings of Edgar Allan Poe's short stories and poems, which were collected together with readings by Basil Rathbone.
He greatly reduced his film work from around 1975, as horror itself suffered a slump, and increased his narrative and voice work, as well as advertising Milton Bradley's Shrunken Head Apple Sculpture. Price's voiceover is heard on Alice Cooper's first solo album, Welcome to My Nightmare from 1975, as well as the TV special Alice Cooper-The Nightmare. He starred for a year in the early 1970s in a syndicated daily radio program, Tales of the Unexplained. He also made guest appearances in a 1970 episode of Here's Lucy showcasing his art expertise and in a 1972 episode of The Brady Bunch, in which he played a deranged archaeologist.
In the summer of 1977, he began performing as Oscar Wilde in the one man stage play Diversions and Delights. Written by John Gay and directed by Joe Hardy, the play is set in a Parisian theatre on a night about one year before Wilde's death. In an attempt to earn some much-needed money, he speaks to the audience about his life, his works and, in the second act, about his love for Bosie, Lord Alfred Douglas, which led to his downfall.
The original tour of the play was a success in every city that it played, except for New York City. In the summer of 1979, Price performed it at the Tabor Opera House in Leadville, Colorado on the same stage from which Wilde had spoken to miners about art some 96 years before. Price would eventually perform the play worldwide and to many, including his daughter Victoria, it was his finest role.
In 1983, Price played the Sinister Man in the British spoof horror film Bloodbath at the House of Death starring Kenny Everett, and he also appeared in the film House of the Long Shadows, which teamed him with fellow actors Christopher Lee, Peter Cushing and John Carradine. While Price had worked with each one of them at least once in the prior decade, this was the first actually teaming of all of them together.
One of his last major roles, and one of his favorites, was as the voice of Professor Ratigan in Walt Disney Pictures' The Great Mouse Detective from 1986. His last significant film work was as the inventor in Tim Burton's Edward Scissorhands (1990).
Price was a lifelong smoker. He had long suffered from emphysema and Parkinson's disease, which had forced his role in Edward Scissorhands to be much smaller than intended.
His illness also contributed to his retirement from Mystery, as his condition was becoming noticeable on-screen. He died of lung cancer on October 25, 1993.