Acting was not Brendon's first choice for a career. When he was younger he had aspirations to be a professional baseball player, but was forced to give up the dream after an arm injury. At the age of 20 he decided to get into acting to help him get over his stuttering problem, but gave it up after two years because, "I couldn't stand the politics in Hollywood." He decided instead to go back to school and study medicine, but this did not work out. He also tried his hand at a variety of other jobs including being a plumber's assistant, veterinary janitor, day care counselor, waiter, and was a production assistant for the TV show "Dave's World". He gave acting another try after being fired from many of these jobs. It only took two months of auditioning before he landed his role of Xander on Buffy.

Brendon was the first person to serve the role of honorary chairperson of the Stuttering Foundation of America's Stuttering Awareness Week for three consecutive years, from 2000-2003. On April 25, 2004 at a Buffy fan convention in Cleveland, Ohio, Brendon announced that he had voluntarily entered rehab for alcoholism. In 2005, Brendon joined the cast of a new Fox sitcom, Kitchen Confidential, based on the Book by chef Anthony Bourdain.

Brendon has an identical twin brother, Kelly Donovan, who is three minutes older than he, and served as his stunt double on Buffy. Kelly also played the part of Xander's double in the episode "The Replacement". He is currently playing one of the Huntsboys for season 2 of American Dragon: Jake Long.