His credits include the roles of Amoukar in Quest for Fire (1981), Salvatore in The Name of the Rose (1986), Vincent in the television series Beauty and the Beast (1987–1990), for which he won a Golden Globe Award, One in The City of Lost Children (1995), When the Bough Breaks (1994), Johner in Alien Resurrection (1997), Koulikov in Enemy at the Gates (2001), Hellboy in both Hellboy (2004) and its sequel Hellboy II: The Golden Army (2008), Clay Morrow in the television series Sons of Anarchy (2008–2013), Nino in Drive (2011) and Benedict Drask in Don't Look Up (2021).

Perlman has also had a prolific career as a voice actor, including the narrator of the post-apocalyptic game series Fallout (1997–present), Clayface in the DC Animated Universe (1992–2003), Slade in Teen Titans (2003–2006), Mr. Lancer in Danny Phantom (2004–2007), Lord Hood in the video games Halo 2 (2004) and Halo 3 (2007), the Stabbington brothers in Tangled (2010), The Lich in Adventure Time (2011–2017) and its spinoff Adventure Time: Fionna and Cake (2023), Xibalba in The Book of Life (2014), and Optimus Primal in both the Transformers: Power of the Primes (2018) animated series and the film Transformers: Rise of the Beasts (2023).

[2] His mother, Dorothy (née Rosen), was a municipal employee, and his father, Bertram "Bert" Perlman, was a jazz drummer and television repairman.

"[7][8] Perlman had a "very close" relationship with his father, who convinced his son he "had to" pursue a career as an actor after seeing him perform in a college production of Guys and Dolls.

His most notable film appearances were in films such as Romeo is Bleeding (1993), The Adventures of Huck Finn (1993), Police Academy: Mission to Moscow (1994), The Last Supper (1995), The Island of Dr. Moreau (1996), Alien Resurrection (1997), Enemy at the Gates (2001), Blade II and Star Trek: Nemesis (both 2002) and two Stephen King adaptations, Sleepwalkers and Desperation.

In 2022, Perlman starred in Steven Brand's noir thriller Joe Baby alongside Dichen Lachman, Willa Fitzgerald and Harvey Keitel.

He has portrayed characters in numerous video games and animated series, and done voice-over work for television commercials.

[18] These include Casper High English teacher and vice-principal Mr. Lancer in Danny Phantom, "Mickey Kaline" in Hey Arnold!, The Lich in Adventure Time, Kurtis Stryker in Mortal Kombat: Defenders of the Realm, Justice in Afro Samurai and various characters in DC Comics based series such as the villainous Slade, a version of DC character Deathstroke in the Teen Titans animated series and again in Justice League: The Flashpoint Paradox, Clayface in Batman: The Animated Series and The New Batman Adventures, Jax-Ur in Superman: The Animated Series, Orion in Justice League and Justice League Unlimited (the former in which he reprised his role as Clayface as well as voice Orion), Sozin in Avatar: The Last Airbender, several villains (Killer Croc, Rumor and Bane) in The Batman, Doctor Double X in Batman: The Brave and the Bold, and Sinestro in Green Lantern: The Animated Series.

He is well known by Fallout fans for narrating the introductory movies in the series, including uttering the famous phrase "War.

[19] In Call of Duty: Black Ops III (2016), Perlman offered his likeness and voice to one of the lead playable characters in the game's popular Zombies mode.

[21] Perlman married Opal Stone, an Afro-Jamaican jewelry designer, on Valentine's Day 1981 and they had two children together: daughter Blake Amanda (b.