The story opens in a post-apocalyptic Southern California, in a hellish world shattered by nuclear war decades before. Several police states have emerged in place of the former United States. Hurricane-force winds above five hundred feet prevent any sort of air travel from one state to the next, and sudden, violent, and unpredictable storms make day-to-day life a mini-hell. Hell Tanner, an imprisoned killer, is offered a full pardon in exchange for taking on a suicide mission—a drive through "Damnation Alley" across a ruined America from Los Angeles to Boston—as one of three vehicles attempting to deliver an urgently needed plague vaccine.
Barry 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." 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.
In 1977, a film loosely based on the novel was directed by Jack Smight. Roger Zelazny had liked the original script by Lukas Heller and expected that to be the filmed version; he did not realize until he saw it in the theater that the shooting script (by Alan Sharp) was quite different. He never liked the movie and was embarrassed by it. However, assertions that he requested to have his name removed from the film (and that the studio refused) are completely unfounded. The movie was released before he ever discovered he did not like it.
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. The film adaptation of Zelazny's novel was also one of several sources of inspiration for the original Fallout, according to designer R. Scott Campbell.