- Perlman was born on 13 April 1950 in Washington Heights, New York. His mother, Dorothy (née Rosen), was a municipal employee, and his father, Bertram "Bert" Perlman, was a jazz drummer and repairman.
- He has been married to Opal Stone Perlman since 14 February 1981 and they have two children: daughter Blake Amanda Perlman (born 1984) and son Brandon Avery Perlman (born 1990). His son produces electronic music under the name Delroy Edwards.
- Has a dog (terrier) named Nigel.
- Does not speak French and was the only American on set of the French film The City of Lost Children (1995). Regardless, he learned all of his lines and delivered them flawlessly.
- Broke a rib while filming the subway scenes in Hellboy (2004). He jumped onto a train that was coming towards him.
- Voiced the mutant villain Clayface on Batman: The Animated Series (1992), a character who, ironically, was a disfigured actor, then voiced the villain Slade on Teen Titans (2003), and also did the voice of the Hulk/Bruce Banner twice on two separate series, one for a guest spot on Fantastic Four (1994) and one for a guest spot on Iron Man (1994), in addition to providing the voice of Orion for Justice League (2001). He then played the comic book character Hellboy in Hellboy (2004). He went on to portray Batman in Justice League Heroes (2006).
- With the creation of Hellboy II: The Golden Army (2008), at age 58, he became the oldest actor ever to play a main superhero.
- Frequent voice collaborator with fellow voice actor Keith David in these computer games: Fallout: A Post-Nuclear Role-Playing Game (1997), Lords of EverQuest (2003), Halo 2 (2004), Halo 3 (2007). Animated series: Aladdin (1994), Fantastic Four (1994), Justice League (2001), Teen Titans (2003). In addition, they have both had a guest appearance on the television series The Outer Limits (1995).
- Is well known for his extensive body of work with acting under prosthetic and has given many actors, like Armin Shimerman (Star Trek: Deep Space Nine (1993)) and Michael Chiklis (Fantastic Four (2005)), advice on how to emote effectively under full-head prosthetic appliances.
- Bears such a striking resemblance to singer and actor Tom Waits, that once, Waits was credited as Perlman on a movie poster.
- In 2012, Perlman once again endured the 4-hour makeup routine required to transform him into Hellboy -- not for a sequel or other acting job but to fulfill the Make-A-Wish request of a six-year-old boy named Zachary who has leukemia. Creature effects house Spectral Motion applied Perlman's Hellboy makeup (and later also made up Zachary as Hellboy as well), and then Zachary got to spend the day hanging out with "Hellboy".
- On 9 November 2016, Perlman announced via Facebook his intention to run for president in 2020.