It's vacation time! But when a visit to the Everglades leads not to the fountain of youth, but a mysterious rampaging monster, the vacation proves anything but restful for Sophia 'Chat' Sanduval and her boyfriend, the Amazing Spider-Man! And things only get worse when Spider-Man finds himself in the odd and potentially lethal position of defending his lethal foe, the Lizard!
We being in medias res, with Spider-Man fighting the lizard in the Everglades in front of a group of enraged people. The Lizard escapes, and Spidey and Chat go looking for him.
In a flashback, Chat and Peter ask Aunt May for permission to visit Chat's cousin, Sarah, a wildlife researcher who works with Curt Connors. Aunt May says yes, so off they go to Florida. But when they arrive, Sarah isn't home. Instead, they find papers on her desk relating to the Lizard. It seems that Connors has reverted to his reptilian self again. They go off to search the town.
After talking to the townspeople (and town animals, via Chat's mutant powers), they discover that there have been a variety of disturbances that can only point to the Lizard. The animals say he is in an abandoned town in the swamp. The townspeople put together a posse to get the Lizard, and Chat and Peter go along.
Back in the present, Chat and Spidey search the abandoned town. They find Sarah, who was also looking for the Lizard and forgot they were coming. She says she was working to help cure Dr. Connors but their experiments ended up turning him back to the Lizard. However, she has a cure, they just need to get him to swallow it.
Chat starts to ask the swamp animals to find him, but then the Lizard jumps out at them. Spidey fights him, and eventually gets him to swallow the serum. Just then, the posse shows up again, and Spider-man tries to get them away from Connors as the potion slowly works. They don't listen to him, but when Chat summons a huge group of animals, they back off.
With Connors cured, they head back home. Peter mentions how tough she was, and that he's glad he he has such a strong girlfriend.