The Rhedosaurus in the film was one of the last surviving members of its species, awakened by a nuclear test in the Arctic. It made its way down the North American coast, destroying everything in its path and ending up in New York, its original home. Rhedosaurus wandered the streets, eating anyone who got too close to it. Attempts to kill it were complicated by an ancient disease it carried; spilling its blood freed the plague, which was almost as deadly as the reptile itself. The Rhedosaurus was eventually killed at Coney Island when a radioactive isotope was shot into a wound on its neck, both fatally wounding it and also neutralizing the disease. As the Rhedosaurus succumbed to the isotope, a fire it started by destroying the machinery of a roller coaster spread across the island. The Rhedosaurus burst free of the burning coaster and roared out defiantly, before finally collapsing to the ground, dead.
Shortly after the Tyrannosaurus rex appeared and began menacing Captain Lee's crew, a Rhedosaurus appeared from over a hill and began fighting the Tyrannosaurus. While this allowed some time for the humans to escape, the Rhedosaurus was severely outmatched, and was quickly killed by the Tyrannosaurus.
The Rhedosaurus' blood contains a disease that can rapidly cause severe sickness and death in humans.
- The Rhedosaurus, along with King Kong, was one of the main inspirations for Godzilla. During the production of the 1954 film Godzilla, its pre-published storyline was very similar to that of The Beast From 20,000 Fathoms and was actually titled The Giant Monster from 20,000 Miles Under the Sea (海底二万哩から来た大怪獣. Kaiteinimanmairu kara Kita Daikaijū)
- Stephen Czerkas constructed a stop-motion Rhedosaurus model for the 1977 film Planet of Dinosaurs, where it battles and is killed by a Tyrannosaurus rex. According to animator Jim Aupperle, "Stephen and I both place the Rhedosaurus among our top favourite of Ray's myriad monsters. We felt that by giving the great Beast a cameo in our film we were acknowledging the immense debt we both feel to Ray. We had to make the Rhedosaurus more of a baby size because one as large as the original would have made a meal of our Tyrannosaurus instead of the other way around."
- A creature resembling the Rhedosaurus briefly appeared in the 1970 film When Dinosaurs Ruled the Earth, though whether it is meant to be an homage to the Rhedosaurus is unclear.
- The Rhedosaurus appeared in the sixth episode of the second season of ABC's Whose Line Is It Anyway?.
- A dinosaur modeled on the Rhedosaurus appears in the second and fourth issues of the IDW comic miniseries Dinosaurs Attack! In the fourth issue, it leads a charge against U.S. forces alongside creatures resembling Godzilla, Rodan, Reptilicus, Gorgo, and Gertie.
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