Spider-Man investigates reports of a strange lizard/human hybrid. Prepare for a showdown with one of Spider-Man's greatest villains, the Lizard!
From a swamp in Florida's Everglades, strange reports of a part-lizard and part-man creature which is attacking people are originating and slowly spreading across the nation. Meanwhile in New York City, Spider-Man is challenged by J. Jonah Jameson through The Daily Bugle newspaper to defeat the mysterious Lizard. Deciding to take up the challenge Peter goes to his boss Jameson and asks if he can travel to Florida to take some photos of the Lizard with his true intent being to fight and defeat the rampaging Lizard. Jameson refuses immediately stating the Lizard is myth and he only printed the headline to increase sales.
The next day Peter while at the Natural History museum intent on learning more about lizard and dinosaurs uses his spider sense to discover two criminals attempting to steal a valuable gem. The criminals then try to kidnap Liz Allan who also happened to be at the museum and Peter changing into Spider-Man effortlessly stops them. Peter then hearing a news broadcast pleading for Spider-Man's help in defeating the Lizard goes to J. Jonah Jameson and convinces him to send a photographer to Florida to cover Spider-Man defeating the Lizard. Jameson now accepting Spider-Man's challenge travels alongside Peter to Florida.
Once in Florida Peter immediately separates from Jameson and changes into his Spider-Man costume and sets off in search of the Lizard. After a difficult encounter with the Lizard he travels to a nearby reptile expert's (Dr. Connors) house to ask for advice. Upon arriving however the doctor is nowhere to be seen and his sobbing wife reveals that the Lizard is in fact Dr. Connor who transformed into the creature after testing a limb regeneration formula on himself. Spider-Man vowing to save the doctor creates an antidote formula and sets off to stop the doctor from creating a reptile army and revert him back to his human self. After a tough battle with the doctor Spider-Man manages to him to drink some of the antidote and he reverts back to his human self. Peter then meets up with Jameson and presents some photos of the Lizard who proceeds to claim they are phoney and the two return home to New York City.