He is known for portraying NYPD Detective Elliot Stabler on the NBC legal drama series Law & Order: Special Victims Unit (1999–2011, 2021–present) and its spin-off Organized Crime (2021–present), for which he was nominated for a Primetime Emmy Award.

He also played Chris Keller on the HBO prison drama Oz (1998–2003), and starred in and executive produced the Syfy series Happy!

Meloni's film credits include 12 Monkeys (1995), Fear and Loathing in Las Vegas (1998), Runaway Bride (1999), Wet Hot American Summer (2001), Harold & Kumar Go to White Castle (2004), Green Lantern: First Flight (2009), 42 (2013) and Man of Steel (2013).

Meloni worked his way up the ladder acting in commercials,[10] short-lived TV series, and bit parts in a number of films.

Meloni was nominated for the 2006 Emmy Award for Outstanding Lead Actor in a Drama Series for his role as Elliot Stabler.

In 2005, he appeared on Episode 107 of MTV2's adult puppet show Wonder Showzen in a series of parody public service announcements warning of the threat of cooties.

"[14] Meloni played Colonel Hardy, a supporting role, in the Superman reboot film Man of Steel, which was released in 2013.

Meloni split his $50,000 charity prize between the Big Apple Circus Clown Care Program and the Montefiore Advocacy Center.

[citation needed] Meloni has appeared in many public service announcements in support of lesbian, gay, bisexual, and transgender issues.

In 2006, Meloni was given the Human Rights Campaign's Equality Award, along with actor Jake Gyllenhaal and director Ang Lee, for his work on behalf of LGBT issues.

[26] Mariska Hargitay, who co-starred with Meloni on Law & Order: Special Victims Unit and remains close friends with him, is the godmother to his daughter.

[28] In 2007, Meloni was inducted into his high school's athletic Hall of Fame as a member of the undefeated 1978 football team, for which he was quarterback.