Remar has spent the majority of his film career playing villains. He portrayed the violent and sexually aggressive character Ajax in the cult film The Warriors (1979), and the murdering sociopath Albert Ganz in the hit 48 Hrs. (1982). (Both films were directed by Walter Hill and co-starred David Patrick Kelly, whose character is named Luther in both). Remar also played real-life 1930s-era gangster Dutch Schultz in The Cotton Club (1984).

In contrast to these roles, Remar starred in the film Windwalker (1980) as the young Cheyenne Windwalker, for which he spoke his lines in the Cheyenne language. He also portrayed a gay man in the film Cruising (1980). In the same year, Remar had a cameo in the Western The Long Riders (1980); his character faced David Carradine's character in a bar fight over a woman Remar's character was married to.

He was the star of the 1986 film Quiet Cool (1986) and was cast as Corporal Hicks in the science-fiction/horror film Aliens (1986), but was replaced by Michael Biehn shortly after filming began, due to Remar's having a drug Problem. For several years, the reason behind his dismissal was reported as "creative differences" with Director James Cameron. At least one piece of footage featuring Remar made it into the final version of the film: when the Marines enter the processing station, and the camera tilts down from the Alien nest, though Remar is not seen in close-up. He is also filmed from the back as the Marines first enter the compound on LV-426 and when "Hicks" approaches the cocooned woman, again filmed from the rear so the viewer is unable to tell it is Remar and not Michael Biehn.

He played Quill, one of the main villains in The Phantom (1996). He appeared in Mortal Kombat: Annihilation (1997), the sequel to the film Mortal Kombat (1995), taking over the role of Raiden from Christopher Lambert. He then followed this with a role in the direct-to-video science fiction movie Robo Warriors (1996). Other films include Psycho (1998), in which he played the patrolman, Drugstore Cowboy (1989), Tales from the Darkside: The Movie (1990), Wedlock (1991), Boys on the Side (1995), The Quest (1996), Rites of Passage (1999), Hellraiser: Inferno (2000), 2 Fast 2 Furious (2003), Fear X (2003), Blade: Trinity (2004), The Girl Next Door (2004). He played a brief role as General Bratt in the prologue of Pineapple Express (2008). He also had a role in the horror movie The Unborn (2009), alongside C.S. Lee, who portrays Vince Masuka in Dexter).

Remar's television appearances include the series Miami Vice, Hill Street Blues, Sex and the City (as the on-again, off-again boyfriend of Kim Cattrall's character), Tales from the Crypt, Jericho, Third Watch, Justice League Unlimited, and Battlestar Galactica. He also appeared as a possessed mental patient in The X-Files ninth-season episode "Daemonicus". He starred as Tiny Bellows on the short-lived television series, The Huntress (2000–2001). He appeared in the miniseries The Grid (2004) as Hudson "Hud", the love interest of Julianna Margulies' character. He had a recurring guest role in the 2006 television series Jericho on CBS. Remar guest-starred in the CBS crime drama Numbers, playing a weapons dealer who later turns good and helps the FBI.

From 2006 to 2013, Remar co-starred in Dexter on Showtime. Remar was nominated for a Saturn Award for Best Supporting Actor for his portrayal of Dexter Morgan's adoptive father, Harry Morgan.

In 2010, he played guest roles as Giuseppe Salvatore in The CW series The Vampire Diaries and as James Ermine, a general for Jericho, a black-ops military contractor, on FlashForward.

Remar was featured in the film X-Men: First Class (2011) and voiced the Autobot Sideswipe in the film Transformers: Dark of the Moon (2011), replacing André Sogliuzzo. He was also cast in the heist film Setup (2011) and starred in the film Arena (2011).

Remar played two different, unrelated characters in Quentin Tarantino's film Django Unchained (2012): his first character, Ace Speck, is killed near the beginning of the film by lead character, King Schultz (played by Christoph Waltz); Remar's second character, Butch Pooch, kills King Schultz near the end of the film. He starred, alongside Emma Roberts, Lucy Boynton, and Lauren Holly, in the thriller film The Blackcoat's Daughter (2015).

He also voiced Vilgax in the animated television series Ben 10: Alien Force and Ben 10: Ultimate Alien, replacing Steve Blum. He guest-starred in Private Practice in 2010, playing a physician named Gibby who works with Doctors Without Borders. On July 23, 2017 Remar was subsequently cast as Peter Gambi on the superhero drama Black Lightning.