Back to School is the twenty-seventh main mission in Marvel's Spider-Man. Immediately after Spider-Man disarms the bombs left in the city during "What's in the Box?", Mary Jane Watson phones him and shares a picture of Isaac Delaney she uncovered; the only problem is she does not know which person he is. In order to figure it out, Peter Parker has to go to an Empire State University Halloween party.
Spider-Man managed to get the name "Dr. Isaac Delaney" from Charles Standish before Sable International stepped in. After passing this information onto Mary Jane Watson, she dug into it while Spider-Man investigated a box at the request of Yuriko Watanabe.
Following this, Mary Jane calls Spider-Man to send a picture of Isaac Delaney and three others at Empire State University, but does not know which one is him, leading Spider-Man to investigate. Along the way, Aunt May tells Peter that she spoke to Rio Morales and loves the idea of Miles Morales working at F.E.A.S.T., as it would give herself time to grieve while her son works.
Spider-Man arrives at Empire State University and finds Delaney on the dance floor dressed as the Lizard, before the Inner Demons take him away. Spider-Man follows, saving students from the Demons on the way, before Delaney meets Martin Li. Li turns into Mister Negative for the first time in front of Spider-Man, who tries to intervene. Li manages to incapacitate him with a massive blast, gaining a name from Delaney as to whom he was working with at Oscorp: Morgan Michaels. With this information in-hand, Li leaves with his Demons, leaving a "negative" possessed Delaney to shoot himself in the head. Players are left to deal with the remaining Demons.
Spider-Man then warns Yuri that Michaels is in trouble. Yuri finds Michaels, but says Sable have him under protection and refuse to tell her where. Afterward, on call with MJ, MJ tells him that she learned Norman Osborn asked Wilson Fisk to build a lab for Devil's Breath that was kept away from regulators, and then asked Fisk destroy all records of it, but she suspects Fisk kept information for eventual blackmail.
Upon arriving at ESU, players are free to search the party-goers as Spider-Man since everyone is in costume. Interacting with someone disguised as Mysterio causes a brief scene as players follow the Mysterio into a mirror maze, followed by Mysterio informing Spider-Man that Delaney is out in the party somewhere. Players then see someone disguised as Vulture standing atop a balcony, and must parkour from a springboard opposite, where he will tell him that Isaac Delaney is dressed as Lizard on the dance floor.
After Spider-Man finds Delaney, before he can talk to him, a student dressed as the Rhino interrupts, keeping him occupied with some of the Inner Demons take Delaney away. The student is easy to deal with (press repeatedly), and then players are free to follow into the Science Center.
Spider-Man watches from above as they escort Delaney through the hall, but must intervene when one of the students decides to ignore the Demons and walk out. A Demon puts a gun to his head, and players must rapidly target it in order to save the student. On the floor, players must face off against the remainder of the Demons. Once dealt with, players need to enter the vent above the laboratory to gain access.
Within the vent, to easily defeat Demons below, the Electric Web can be used to knock out the lighting before entering the room. As long as Spider-Man remains in the shadows, he seems to retain an advantage in the fight. When the Demons are dealt with, Spider-Man learns Delaney has been taken further into the building. At this point, players exit the room via a window, to track Delaney from the outside as he is escorted down the halls. Another vent allows entry to the room that the doctor is taken into, where he is met by Martin Li.
Finding Li leads to a cutscene, followed by a battle with Demons and then a chase with Li. The chase outside only results in party-goers influenced by his negative power, and players must battle them as well. Battling the student dressed as Rhino leads to a cutscene as the mission ends. A call with Mary Jane then unlocks to the next mission, "Spider-Hack".