Sudden, violent, and unpredictable "garbage storms," and giant, mutated animals and insects make day-to-day life treacherous.

Hell Tanner, an imprisoned Hells Angels member, is offered a full pardon for his crimes in exchange for taking on a suicide mission: a precarious drive through Damnation Alley, a narrow passage relatively free of lethal radiation, across a ruined America from Orange County, California to Boston, as part of a convoy of three Landmaster vehicles (fitted with various rocket launchers, flame-throwers, machine guns, and slicing implements) attempting to deliver an urgently needed plague vaccine to survivors.

Barry N. Malzberg found the book "an interesting novella converted to an unfortunate novel," faulting it as "a mechanical, simply transposed action-adventure story written, in my view, at the bottom of the man's talent.

"[1] Zelazny himself agreed with Malzberg, stating that he preferred the novella and only expanded it at his agent's request to make it more viable for a movie deal.

The setting and premise of the 2011 Lonesome Road add-on for the post-apocalyptic computer game Fallout: New Vegas was inspired by Damnation Alley, according to lead designer Chris Avellone.