He had guest roles on shows such as Criminal Minds, Law & Order: Special Victims Unit, The Simpsons, and Will & Grace, as well as a recurring role voicing Rick Jones in The Incredible Hulk (1996–1997) from Marvel Comics, and also appeared in various films, including Buffy the Vampire Slayer (1992), 8 Seconds (1994), The Fifth Element (1997), The Final Storm, The Beat Beneath My Feet (2016), and Once Upon a Time in Hollywood (2019), which was his final feature performance and earned him a Screen Actors Guild Award nomination.

[8] In 1990, Perry got the role of the brooding millionaire's son Dylan McKay on Fox's teen drama Beverly Hills, 90210.

[10] While starring in 90210, Perry had a supporting role in the original film version of Joss Whedon's Buffy the Vampire Slayer (1992).

[citation needed] From 2001 to 2002, Perry starred in the HBO prison drama Oz, as Reverend Jeremiah Cloutier.

[8] In 2007, he landed the role of Tommy "Santa" Santorelli on the film The Sandlot: Heading Home, and he appeared in the 2008 western A Gunfighter's Pledge.

Perry parodied himself in "The Story on Page One", an episode of Family Guy, in which he sues Peter Griffin for calling him gay in a newspaper article.

[28] His other voice work includes The Incredible Hulk as Rick Jones, Biker Mice from Mars (which also starred fellow 90210 co-star Ian Ziering), Mortal Kombat: Defenders of the Realm, and The Night of the Headless Horseman.

[29][8] Perry guest-starred as gay characters in the sitcoms Spin City (1997) and Will & Grace (2005); in the former, he appeared as Carter Heywood's ex-boyfriend who subsequently fell in love with a woman, and in the latter he played a birdwatcher who catches the eye of Jack McFarland.

[31] In 2008, Perry guest-starred as rapist Noah Sibert in the season premiere of the television series Law & Order: Special Victims Unit.

In late 2009, Perry starred in The Killers' music video for their fourth annual Christmas single, "¡Happy Birthday Guadalupe!".

The project also featured a large ensemble of other well-known Hollywood actors, including Jim Caviezel, Louis Gossett Jr., John Rhys-Davies, Jon Voight, Gary Sinise, Jason Alexander, Christopher McDonald, Marisa Tomei, Stacy Keach, and John Schneider.

[51][52] On February 27, 2019, Perry suffered a massive ischemic stroke at his home in Sherman Oaks, Los Angeles, and was taken to Providence Saint Joseph Medical Center in Burbank.

Perry is buried in an eco-friendly mushroom burial suit which the manufacturer states can remove polluting toxins from the body while naturally breaking it down.

[54] In the aftermath of his death, the Reelz channel announced a documentary titled Luke Perry: In His Own Words.