Vrača se eden najbolj priljubljenih stripovskih junakov. Najstnik Peter Parker v šoli nikakor ne najde pravih prijateljev, razumevanje najde le pri dolgoletni prijateljici Gwen, ki ji brez uspeha skuša izpovedati svoja ljubezenska čustva. Življenje se mu postavi na glavo, ko odkrije kovček dolgo pogrešanega očeta. Ker želi raziskati očetovo izginotje, ga sledi vodijo do očetovega nekdanjega sodelavca, dr. Connorsa, toda soočenje z njegovimi nenavadnimi poskusi Petra spremeni v superjunaka. Poleg soočanja s svojo novo identiteto se mora Peter spopasti z grozljivim stvorom, ki želi uničiti mesto.
Peter Parker (Garfield) is an outcast high schooler who was abandoned by his parents as a boy, leaving him to be raised by his Uncle Ben (Sheen) and Aunt May (Field). Like most teenagers, Peter is trying to figure out who he is and how he got to be the person he is today. Peter is also finding his way with his first high school crush, Gwen Stacy (Stone), and together, they struggle with love, commitment, and secrets. 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 (Ifans), 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.