Peter Parker and his college science professor Dr. Curt Conners explore neogenics as a method of limb regeneration. But while experimenting on himself, Connors accidentally becomes the Lizard, a half-man, half-reptile monstrosity that terrorizes Manhattan and subsequently kidnaps his own wife. Spider-Man's task is doubly difficult because he doesn't want to hurt the good friend he knows is trapped inside...but he must stop the inhuman beast who is out of control.

The Master of Illusion, Mysterio has fooled the city and J. Jonah Jameson into thinking Spidey has turned to crime. However Spidey manages to find Mysterio only to be brought to a trap of special effects.

A space shuttle piloted by J.J.'s son, John Jameson, crash lands on the Tri-Borough Bridge carrying two strange meteors -- One that could provide a new nuclear fuel and one that contains an alien substance. The first is stolen by the Kingpin's henchman, the Rhino, just as Spider-Man arrives to save Jameson and the co-pilots. When the Rhino sends the aircraft off the bridge, Spider-Man emerges from the water with a dark stain covering his costume. Exhausted, he heads for home, only to awaken hanging from a skyscraper, now clothed in a black version of his costume.

When Aunt May is slightly injured by one of the Hobgoblin's pumpkin bombs during the kidnapping of Harry, Spider-Man enters the fray with a vengeance. After several battles, the trail leads Peter to Oscorp and Harry's own father. For Peter, rescuing his friend is easy compared to explaining to Harry that his own father is involved.

Dr. Curt Connors is set to study the Tablet of Time, a recently discovered ancient artifact that is said to restore a person’s youth. Dr. Connors believes that it can cure Spider-Man’s mutagenic transformations with the tablet.

With the Tablet of Time, Silvermane's youth is restored, but he continues to grow younger until he finally becomes an infant.

Under the psychiatric care of Dr. Kafka, Eddie Brock has come to believe that Venom is a figment of his imagination. Then Baron Mordo tempts Eddie -- reunification with the alien symbote that makes him as powerful as Venom.

Spider-Man and Venom must put aside their differences and help Iron Man stop Carnage and Baron Mordo from releasing Dormammu.