He made his acting debut in Jean-Jacques Annaud's film Quest for Fire (1981). His breakthrough role came when he played Vincent in the TV series Beauty and the Beast, opposite Linda Hamilton. This earned him a Golden Globe and a large fanbase. He has since starred in many films, though his first major lead role came in 2004 with Hellboy. The director Guillermo del Toro had to fight to secure the role, as the studio wanted someone more well-known such as Vin Diesel.

He has been married to Opal Perlman since February 14, 1981, and he has two children, Blake Amanda (born 1984), and Brandon Avery (born 1990).

As well as onscreen acting, Ron Perlman lends his considerable voice talents to numerous video games and animated series, most notably as Slade in the Teen Titans animated series and Vice Principal Lancer in Danny Phantom. He has also voiced Clayface in Batman: The Animated Series, Jax-Ur in Superman: The Animated Series, Orion in Justice League animated series, and Killer Croc in The Batman. His video game credits include Lord Hood, the captain general of the earth's space defense fleet in Halo 2, Jagger Valance in The Chronicles of Riddick: Escape from Butcher Bay, and most recently in Incredible Hulk: Ultimate Destruction he voiced the player's nemesis - Emil Blonsky, who later becomes irradiated and turns into the Abomination. In the Fallout role-playing games, he is well known by fans for uttering the famous phrase "War, War never changes".

Though clearly a talented actor with a wide range of performances under his belt including both heroes, villains, cynics and the sincere, many feel that it is his unusual face, the archetypal craggy or granite like face (marked by an extremely large chin and jawline), that has prevented him from achieving leading man status . Undaunted and good natured, Perlman recognizes that his career has some unusual roles on the resume and insists that he isn't bothered by how his career has turned out . Many who have met and worked with him comment that he is a very friendly man with a colorful sense of humor and a nuanced spoken delivery , a vital asset given the roles where his face has been obscured by prosthetics. It has been noted that the stocky, 6'2" actor is often cast as characters who are either deformed or not human, presumably on account of his face, making him something of the modern day Lon Chaney. His willingness and ability to express emotion through make up has made him a favorite among cult followers.