It has been a few years since the events of Spider-Man 3. Peter is still coping with the death of Harry Osborn, and has renewed his relationship with Mary Jane. His life finally seems to be settling.
Curt Connors finally finishes a serum that will re-grow his arm, and help others like him with funding provided by the new chairman of OsCorp Adrian Toomes who pressured him into finishing it quickly. At first it seems to work but at home he turns into the Lizard. Spider-Man confronts the Lizard, but it escapes and Spider-Man discovers it is Dr. Connors.
Toomes knows that the Lizard is Connors and realizes that he needs him eliminated and then hears about a world renowned hunter named Sergei Kravenoff.
Kravenoff finishes a hunting exhibition in Africa when one of Toomes' men brings him to the states where he meets with Toomes who hires him to kill the Lizard to help cover up the accident.
Kraven and the Lizard have their first battle, and Kraven is forced to retreat being overwhelmed and takes aim at Lizard but Spider-Man stops him, making Kraven believe Spider-Man to be a worthy adversary.
Meanwhile Lizard begins experimenting on people in the sewers, turning them into lizard creatures like himself.
Spider-Man must now face the world's most deadly animal, and most deadly hunter.
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