Burden grew up in the industrial rust belt of the Northeast United States. After twenty years in Buffalo, Pittsburgh, New Jersey, Milwaukee, Akron, and Sharon, Pennsylvania, he moved south to Atlanta, where he has lived since. In 1976, Burden graduated from University of Georgia, in Athens, with a degree in journalism and minors in advertising and political science.

Burden’s best-known creation, Flaming Carrot, has received some scholarly recognition: a cover story and interview in Atlanta's prestigious Art Papers; an original cover drawing in Sotheby's art auction; and reviews in The Village Voice literary supplement. Flaming Carrot has even appeared as a Jeopardy! answer.

Burden's Mystery Men was the subject of a 1999 film adaptation, directed by Kinka Usher and starring Ben Stiller and Geoffrey Rush.

Besides Flaming Carrot Comics and Mysterymen, Burden wrote an Gumby story, a two-part Cholly & Flytrap story with Arthur Suydam, and Robot Comics, a series which was reprised as the "Robot Crime" story for the 20th anniversary of Heavy Metal.

Burden also inadvertently affected the name of the cartoon character, SpongeBob SquarePants, whose creator Stephen Hillenburg had initially thought to name him "SpongeBoy", until he discovered that Burden had already trademarked the name. Hillenburg eventually named him Spongebob in reference to Burden's given name, Bob.

Bob Burden has also produced some prose work, including a short story called "You've Got Your Troubles, I've Got Mine" and an anthology of short stories by various writers, including Stephen King, called Dark Love, from Penguin Books.

Burden's works have won numerous awards including the Inkpot Award for Outstanding Achievement in Comic Arts, the ACE Award, and perhaps the most prestigious award in comics, the Will Eisner Comics Industry Award for the Best Single Issue (Gumby's Summer Fun Special). Burden also has two 1998 Eisner Award Nominations, for Invincible Man and Flaming Carrot's Greatest Hits Volume Three.