At the start of this issue, Spider-Man is swinging around, worrying about his problems since Gwen Stacy seemingly returned, and Aunt May had to be put in hospital. He jokingly thinks to himself that he should get a quiet place of his own in the country away from his problems, before realising that perhaps that's what he does want. He then notices a TV in a store window which may have the solution he wants, and swings down to it. On the TV is a news report about the Man-Thing, speculating on its orgin and giving a few details about its public appearances. After hearing that the Man-Thing has mostly been seen in the vicinity of Citrusville, Florida, Spider-Man decides that he'll try and convince J. Jonah Jameson to send him on a photo assignment to take photos of Man-Thing, which will more or less get him a free trip to Florida.
J. Jonah Jameson agrees to Peter's idea, and makes plans to pay for Peter's trip. Peter then calls up Curt Connors, as Spider-Man has mentioned Peter to Connors before, and tells Connors that he's doing a photo story on the Man-Thing, and would appreciate his help. Curt agrees, and as he hangs up the phone, he starts thinking about the Man-Thing. Peter then calls up Mary Jane to tell her that he'll be gone for a while, which disappoints her. Before Peter can leave the Daily Bugle, Betty Brant tries talking to him about Gwen Stacy having returned, but Peter isn't in the mood to talk about her. Meanwhile, Curt is still thinking about the Man-Thing when he accidentally knocks over a beaker full of an experimental serum. A gas billows out from the serum, which engulfs Curt and transforms him back into his deadly alter ego- the Lizard!
Curt's wife Martha hears the crash, and enters Curt's lab to find the Lizard there. The Lizard knocks Martha aside then heads to the swamp, as he finds it hard to concentrate in the house. After reaching the swamp, the Lizard wonders who Martha could have been, before thinking that he wants to find the Man-Thing and use him against the world. Back in New York, Spider-Man swings to Betty Brant's apartment, where the recently returned Gwen is living. Changing to Peter Parker, he apologises to Gwen for acting so oddly when she first returned, but Gwen bursts into tears and says that that's only part of the problem. She tells Peter that she's lost two years of her life, as she has no idea who the President of the United States on TV is. She then asks Peter whether she could be going mad.
Back in Florida, the Man-Thing is in the swamp and heading towards a man named Edmond at the outskirts of the swamp. Edmond thinks to himself that he's failed completely in life, and that he's going to kill himself in the swamp because he can't cope with the stress. He then wonders where he went wrong, and thinks back to how he started up his own chemical company after studying for a biochemistry degree at college and getting married. Although he got defence contracts and other such things, his life collapsed at the start of the recession, and he and his wife were bankrupt. He then thinks that because his pride and dignity are gone, the only thing he can do is kill himself. By now the Man-Thing has reached Edmond, and he panics when he notices it. After the Man-Thing attacks a crocodile, it heads further into the swamp. Edmond then decides that the Man-Thing may be the only chance to turn his life around.
By this time, Peter has arrived in Florida, dressed in his Spider-Man costume. He's already been told by Martha Connors over the phone that Curt turned back into the Lizard, and as he wonders whether he'll run into the Man-Thing or the Lizard first, the latter appears and attacks. The Lizard is strong enough to take on Spider-Man quite easily, and is choking Spider-Man with his tail when Martha Connors steps out of her and Curt's house to see the battle. Martha manages to use a high-pressure water hose to distract the Lizard, giving Spider-Man the opportunity to tie the Lizard to some trees with his webbing. Whilst this is happening, Edmond is following the Man-Thing, planning to bring it back to civilisation and make money out of it. As he tries to work out how he can knock the Man-Thing out, Edmond suddenly notices other reptiles from the swamp following the Man-Thing, as if they were being called by someone or something.
As Spider-Man comforts Martha, the Man-Thing and the rest of the reptiles arrive, which the Lizard says is due to his mental commands. Whilst the reptiles all free the Lizard from Spider-Man's webbing, the Man-Thing attacks Spider-Man, as per the Lizard's mental commands. Spider-Man thinks that fighting the Man-Thing will be easy, as it's a mindless monster, but this proves to be wrong as the Man-Thing is immune to pretty much all of Spider-Man's attacks. As Spider-Man fights the Man-Thing and the Lizard is being freed by the remaining reptiles, Edmond arrives, and is shocked by the battle he has stumbled onto. Martha notices Edmond, and asks him for his help. At first Edmond says that he won't be able to do anything, as he's only a chemist, but upon hearing this, Martha convinces him to come with her and make the antidote to turn the Lizard back into Curt.
By now the Lizard has been freed, and Spider-Man thinks that he won't be able to fight both the Lizard and the Man-Thing, until the Man-Thing attacks the Lizard. Spider-Man realises that the Man-Thing provides a feedback to the strongest emotion around, and is attacking the Lizard because his emotions are so strong that they are overloading the Man-Thing's emotional "circuits". The Lizard, Man-Thing, and Spider-Man all engage in a three-way battle whilst Edmond tries making the formula to transform the Lizard. Edmond thinks at first that it's futile, since it's such a delicate procedure, but upon hearing from Martha that Spider-Man was the one who developed the serum, he becomes determined to recreate it. As Edmond finishes making the formula, the Lizard mentally commands the reptiles to attack Spider-Man whilst he battles the Man-Thing.
As Spider-Man struggles with the reptiles, Edmond runs out of the house with the formula to transform the Lizard. Unfortunately, Edmond stumbles on one of the Lizard's mind-controlled snakes, and thinks that he's failed as he always does as the serum flies out of his hands. Fortunately, Spider-Man has noticed Edmond, and catches the serum with his webbing, before swinging it into the Lizard. The serum seeps through the Lizard's scales and transforms him back into Curt Connors. As the story ends, Spider-Man says that the Man-Thing (who is leaving the battle scene) isn't just a mindless monster as people think, whilst Edmond agrees, saying that whilst he had thought that his life was over, he now realises that it's only just beginning.
This issue also reprints Amazing Spider-Man #21.