Curtis’ first role came in the 1983 hit film Risky Business, however, he is probably best known for his role of Booger in Revenge of the Nerds and its sequel Revenge of the Nerds II: Nerds in Paradise. He later reprised his role as Booger in the 1992 television movie Revenge of the Nerds III: The Next Generation and the 1994 television movie Revenge of the Nerds IV: Nerds in Love. His other films include Better Off Dead, Big Bully, One Crazy Summer, Bad Medicine, National Lampoon's Van Wilder, Smokin' Aces, DodgeBall: A True Underdog Story, Jingle All The Way, and Southland Tales. He also had a recurring role as Herbert Viola on the television series Moonlighting, and played the part of Ahmet Ertegün in the biographical film Ray (2004). He currently voices the character ‘Snot’ on American Dad!, a parody of his role from Revenge of the Nerds. He was the voice of the title character in Dan Vs.
In 1997 He played "Farley", a fictional composite character based on members of Elvis Presley's real entourage in the cult-comedy film Elvis Meets Nixon. He also had a part as "Russ" on the short-lived TV show Reaper.
From 2008–2013 he portrayed Dr Parker/Dr Dawson on The Game.
Armstrong and former Revenge of the Nerds co-star Robert Carradine hosted the TBS reality TV competition series King of the Nerds. The series, which pitted contestants with expertise in a variety of geek interests to see who would be crowned with the eponymous title, premiered in January 2013.
In May 2013, Armstrong appeared as Dr. Foster in an episode of New Girl.
Curtis had a recurring role as the angel Metatron in several episodes in the 9th, 10th and 11th seasons of Supernatural.
Most recently he voiced Ezekiel the Cockroach in the DC television series Doom Patrol.