Brubaker's first work in comics was for the independent publishers Blackthorne Comics and Slave Labor Graphics for which he wrote and drew Pajama Chronicles and Purgatory USA respectively. In 1991, he became a contributor to Dark Horse Presents. Among those contributions was the three-part serial An Accidental Death, which won two Eisner Awards in 1993.

DC Comics imprint Vertigo published Brubaker's Prez, Smells Like Teen President in 1995 and four-issue series Scene of a Crime in 1999. Brubaker signed an exclusive contract with DC in 2000 and began mainstream superhero work on such series as Batman and Catwoman, a character revamped by Brubaker and artist Darwyn Cooke.

In 2003, Brubaker teamed up with writer Greg Rucka to create the Gotham Central series, which focuses on the Gotham City Police Department.

In 2004, free from his contract with DC, Brubaker began to contribute to DC's competitor Marvel. His first work with the publisher was a relaunch of the Captain America series, which famously climaxed in the hero's death.