Qualls has also had starring roles in the films I'm Reed Fish (2006), Delta Farce (2007), Amigo (2010), Small Apartments (2013), and Buster's Mal Heart (2016).

Qualls had main roles as Police Officer Davey Sutton on the TNT crime series Memphis Beat (2010–2011) and Billy Nugent on the FX and FXX sitcom Legit (2013–2014).

According to Qualls, the chemotherapy at an early age sped up his metabolism and affected his growth, "It stopped my development," which explains his slender frame.

[1][2] After graduating from Coffee County Central High School in 1995, where he was an active member in the Red Raider Band, Qualls attended King's College London, where he studied English literature.

[7] His television work includes eccentric hunter Garth Fitzgerald IV on Supernatural and appearances on Monk, Scrubs, Criminal Minds, Lost, Law & Order: Criminal Intent, CSI: Crime Scene Investigation, Numb3rs, My Name Is Earl, Breaking Bad, The Big Bang Theory, and Memphis Beat.

In January 2020, Qualls came out as gay on his Twitter account, stating he was "tired of worrying about what it would do to my career,"[11] after announcing it at a Jim Jefferies show in San Diego.