诺曼·奥斯本聘请斯宾塞·斯迈思设计一台能够摧毁蜘蛛侠的机器——黑寡妇蜘蛛杀手。 但是当闪电汤普森穿上蜘蛛侠服装作为派对噱头时，致命机器发现了他，他代替彼得被带走了。

斯宾塞·斯迈思死后，他的儿子阿利斯泰尔求助于金并帮助他报复蜘蛛侠和其他他认为应对父亲之死负责的人。 他俘虏了埃迪·布洛克、J·乔纳·詹姆森、诺曼·奥斯本和闪电汤普森。 然后，他将目光转向蜘蛛侠，并派出三名杀手追捕他。 蜘蛛侠在与他们单独作战时只能设法坚守阵地。 然而，当他们组合成超级杀手并将他带到斯迈思时，他就没那么幸运了。

Norman Osborn hires hitman and thief, the Hobgoblin, to take out Osborn's "silent" partner, Wilson Fisk (the Kingpin). When he fails in the attempt, the Hobgoblin changes sides, kidnapping Norman's son, Harry. Harry just happens to be best friends with Peter Parker.

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.

Adrian Toomes wants revenge when Norman Osborn attempts to take over his company, Toomes Aeronautical. He becomes the Vulture and immediately kidnaps Norman's son, Harry. Will Spidey be able to rescue Harry from the Vulture's youth stealing talons?

Spider-Man seeks Curt Connors aid to help reverse the aging effects of the Vulture's talons. The Vulture meanwhile sporadically turns into the man-spider from the mutagenics he absorbed with Spidey's youth. At the same time, the Scorpion grabs Dr. Farley Stillwell to seek a cure for his own mutation. With Doc Connors in the middle, feeling the onset of his own his reptilian transformation, will everyone be cured in time for Peter to meet up with Mary Jane as she confronts her wayward father???

Worried that Kingpin is going to eliminate him after the botched framing of Peter Parker, Alistair Smythe arranges a meeting with Spider-Man to give him information about Kingpin. However, when Spidey arrives, he discovers Smythe has been turned into a cyborg. Part man, part machine, he is now the ultimate spider-slayer! However, when his programming malfunctions, he goes after the man he feels responsible for his father's death...Norman Osborn! Peter must fight a crazed Smythe, as well as his feelings when he discovers Mary Jane, the woman he loves, and Harry, his best friend, are engaged!