The Amazing Spider-Man is the story of Peter Parker, an outcast high schooler who was abandoned by his parents as a boy, leaving him to be raised by his Uncle Ben and Aunt May. Like most teenagers, Peter is trying to figure out who he is and how he got to be the person he is today. As Peter discovers a mysterious briefcase that belonged to his father, he begins a quest to understand his parents' disappearance - leading him directly to Oscorp and the lab of Dr. Curt Connors, his father's former partner. As Spider-Man is set on a collision course with Connors' alter-ego, The Lizard, Peter will make life-altering choices to use his powers and shape his destiny to become a hero.

Simon Phoenix, a violent criminal cryogenically frozen in 1996, has escaped during a parole hearing in 2032 in the utopia of San Angeles. Police are incapable of dealing with his violent ways and turn to his captor, John Spartan, who had also been cryogenically frozen when wrongfully accused of killing 30 innocent people while apprehending Phoenix.