He got his big break as an actor when he landed the role of Xander Harris on the hugely successful TV series "Buffy the Vampire Slayer" (1997). The series ran from 1997 until 2003, garnering a huge cult following as well as a large fan base for Brendon. Brendon and his twin Kelly Donovan appeared together in the episode "The Replacement", in which Xander has to cope with having a seemingly sinister double.
 Outside of "Buffy the Vampire Slayer" (1997), Brendon became a spokesperson for the Stuttering Foundation of America, appearing in a print campaign for the organization. His first major role in a feature film came with the Charles Busch satire Psycho Beach Party (2000). Brendon has also starred in the ABC Family Channel original movie Celeste in the City (2004) (TV).