Both the short story and the novel open in a post-apocalyptic Southern California, in a hellish world shattered by nuclear war decades before. Several surviving 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 urgently needed plague vaccine.

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 didn't 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 didn't like it.

The novel Hardwired by Walter Jon Williams is an homage to Damnation Alley. The two authors (Zelazny and Williams) later became good friends.

The 2000 AD comic had a long running Judge Dredd story arc that was an adaptation of the story (with the journey in the reverse direction), in which Dredd and Spikes Harvey Rotten (the greatest Punk alive) journeyed across the Cursed Earth between Megacity 1 (on the U.S. East Coast) to Megacity 2 (on the West coast) to deliver a vaccine to the 2T(Fru)T virus. It was also subject to a number of copyright violations.

The Hawkwind album Quark, Strangeness and Charm contains a song inspired by the story.