The story follows Peter Parker, a 23-year-old college graduate and research assistant who gained superhuman abilities after being bitten by a radioactive spider. Peter is in his eighth year of crime-fighting under his super heroic alter ego of Spider-Man, who has become highly experienced at this point, but struggles to balance his superhero and personal lives.
Peter Parker / Spider-Man gets alerted to a robbery at a snake shop and chases a kid down. After catching the kid and realising that he had stolen rubber snakes, Spider-Man asks the kid a few questions, he says his name is Andy and gives him a tip from about Scorpion’s hideout in a construction site. Spider-Man then goes to the hideout only to find a man in black there, he uses identical moves and skills to Spider-Man and ends up kicking Spider-Man to the ground, and escapes shortly after. Spider-Man leaves and goes to find Andy, only to discover that he's dead in the street, a police officer points a gun at him and says that he is the prime suspect in the murder, however she reveals to him that she knows that he didn't do it and she is revealed to be Lt. Yuri Watanabe. Watanabe shows him security footage with timestamps that show Andy being shot, it looks like Spider-Man, yet he knows he was on the way to the hideout at that time, he tells her about the construction site's address, which shocks her as the construction site is owned by Wilson Fisk. Spider-Man then reflects on how since his early days as Spider-Man he had been convinced Fisk was the Kingpin of Crime, and has been wanting to put him behind bars ever since, looking for evidence. He had files, laptops, photographs and witness reports, but it wasn’t enough, Fisk’s Lawyers turned news outlets to Spider-Man, making it out he was the criminal trying to bring down a legitmate businessman. Fisk then left the country for years after that and came back last year to create the Fisk Foundation, a charity aimed at improving the lives of citizens in New York, with Fisk claiming he was a changed man. Watanabe and Spider-Man decide to work together to bring down Fisk and start a partnership that would last for a long time.
Peter Parker, Harry Osborn and Mary Jane Watson are all good friends but Parker thinks highly of Osborn in particular and that he is a good person. Osborn is moving to Europe to pursue other life interests and to get away from his father. Parker visits Osborn to ask where Watson is since she isn't answering her phone, to which he replies by asking why he's not with her right now, Parker laments that he has never told Osborn that he was Spider-Man, not because he didn’t trust him, but because he didn’t have to tell him and it kept him safer that way, he is also afraid that his father may find out if he told him as well. Parker is suspicous of Norman Osborn notbe cause he thinks he's neccesarily bad, but because he likes power too much. Osborn tells him that Watson is auditioning for the Daily Bugle in Hell's Kitchen since she wants to become a journalist, however even though she knows Martial Arts, Parker is protective of her in such a dangerous area. Parker gets the adress from Osborn and visits Watson, she's writing a puff piece on Fisk.
Fisk saved a girl called Maya Lopez from a foster center, she is deaf and he watches her fight for entertainment. She is very capable, and a good fighter, she thinks highly of Fisk, but knows he has a dark side, however Fisk is trying to keep his anger under control so that he can maintain a good public image. After one of her fights, Lopez went onto her laptop which has a program that hacks into all the cameras in Fisk Tower. She see’s Fisk look at footage of 2 men fighting on a construction site, and she recognises one of them as the man that killed her father. She walks into Fisk's office and looks at the video, prompting her to ask Fisk who that was, he tells her the man who killed her father was Spider-Man, he also tells her that the other man is someone he has trained, Lopez interrupts and says that she too has also been trained for revenge. She asks how the man in black moves like Spider-Man, Fisk says they did medical experimentaions on him, something that he would not risk on Maya too. She also gets his name, Michael Bingham, and learns that Bingham is very unstable. Fisk says that he will send a document about him to her for her to read.
Theodore Peyton, the man who runs the finances at the lab where Parker works, wakes Parker from his sleep and tells him off for it, Parker starts to wonder if Spider-Man is getting in the way of his life, he is also currently working on fully functional prosthetic limbs where he works. Anika Adhikari starts work at the lab.
Mary Jane Watson used to think Spider-Man’s heroics were thrilling, but now realised that they stopped her from doing her own things in her own life which is why she is pursuing Journalism. Parker did use to work as a photographer for the Bugle. Watson lands the job at the Bugle but is strictly told by Robbie Robertson that she won’t pursue Fisk.
Maya Lopez decides to track down Michael Bingham and see’s him stick a homeless man to a wall, she wonders what the point of doing that was. She then tracks him to his apartment and knocks on the door with a soda can because she saw pizza get delivered, she asks why he is imitating Spider-Man to which he claims he is Spider-Man and not an imitation.
Watson and Parker have dinner together at a sandwhich shop and Watson wants to tell him something but she gets interrupted by a call from Yuri Watanabe. Parker goes and meets up with her, she wants him to find a payroll file in Fisk Tower overnight, Parker wants to stop Fisk as soon as possible and hopes the city won’t need him as Spider-Man anymore. He goes into Fisk Tower and gets the file, but hears Fisk having a conversation and checks where he is, he webs up some cameras on his way there. Fisk is talking to Lopez but Peter can’t make sense of the conversation, later he asks Yuri to look into the name “Maya”. Lopez notices the webbing on the cameras and decides that something needs to be done.
Peter Parker goes down to F.E.A.S.T to meet Aunt May and is introduced to Martin Li for the first time.
Parker later goes to see Harry Osborn in a coffee shop as it will be one of the last times he sees him before he goes to Europe. He tells Harry he feels like something is off between him and Watson. Norman Osborn ends up in the Coffee shop as well, and offers Parker a job to work at Oscorp to which he declines.
Parker has a conversation with Adhikari about himself and his troubles.
Mary Jane Watson walks into Fisk Tower and is greeted by Lopez, going against what the Bugle said about not investigating Fisk, she shows up anyway.
Lopez goes and meets with someone outside of Fisk Tower, that person is J. Jonah Jameson. He says he wants to take down Spider-Man and Lopez says that she wants to help him, she then tells him that they will give him his own radio broadcast to reach more people.
Watson interviews Fisk and learns that Martin Li has funding from Fisk for the F.E.A.S.T shelter.
Bingham breaks into Fisk's office and gets passed security with ease, much to the annoynace of Fisk. Fisk is irritated that he can't intimidate Bingham and is also suspicious when Bingham knew Lopez was deaf.
Anika Adhikari follows Parker to the sandwich place that he and Watson are having dinner at, however, there is a hostage situation in an auction house called Rosemann’s and so Parker runs off. The Hostage situation is a decoy however and Shocker bursts into the Sandwich place, Bingham then arrives and pretends to be Spider-Man, he then states that if a few hostages die it doesn’t matter as long as he will get Shocker. They then pretend to fight and the sandwich place blows up with people dying including Adhikari and the restaurant is destroyed. Watson says to Parker on the phone that she is okay but Parker has no idea why she wouldn’t be as he is unaware of the situation. A Woman gives an interview stating Spider-Man said he didn’t care who was hurt and even threw a man at Shocker.
Michael Bingham has a meeting with Fisk, Fisk tells Bingham that hiring shocker was risky and also that the attack was sloppy but Bingham ignores him and is generally disrespectful towards him, which Fisk and Lopez, who is watching through the cameras, are angered by.
Bingham laments about his past, how he had grown up poor and without a father, how the other kids at school picked on him and how his mother had gotten cancer and died. He then thinks back to when he came to New York, and when he saw Spider-Man swinging and how he thought that he should've been up there swinging and not an imposter, he from then on thought that he was the real Spider-Man and Parker was a fake. After a while of living in the city, a woman recruited him into an experimentation.
Spider-Man decides to track down Shocker and ends up in the Bar with No Name. He goes in to ask questions and notices Electro and Scorpion in there, he then asks where Shocker is and Scorpion comes to escort him out, he then proceeds to say that he wants to help Spider-Man as weird stuff is going on in the city with disappearances. Scorpion directs Spider-Man to Shocker, who looks depressed. Spider-Man asks whats going on and Shocker says his suit was stolen a month ago. Spider-Man then finds the fake Shocker and discovers he is an actor called Phil Simons, he says he didn’t know about the bombs.
Wilson Fisk calls Watson in for another meeting, this time regarding a piece she had written which spoke badly about Fisk. He says that she might have a role in the company in the future if she keeps in line, she declines his offer. On her way out of the building she notices security teams around the building.
Lopez meets with Jameson again and he reveals that he know that the money is coming from Fisk, he says that if he hears anything about Fisk, he'll leave and start a podcast. Bingham is watching them.
Spider-Man goes around the city stopping Fisk's operations in an attempt to find out more information, however reports are being made putting him in a bad light. Watson tells him about the security at Fisk Tower.
Maya Lopez takes the alias of Echo and paints a white hand on her face, she follows Spider-Man as he investigates the lead Watson gave him. Echo and Spider-Man fight and he notices how she copes his movements precisely but also notices her lack of enhanced power.
Parker tells Watson about Echo the day after and she recognises her as Maya Lopez, Parker wants her to stop investigating Fisk as he sees it to be too dangerous but Watson thinks he is being overprotective, this is what she wanted to talk about, they come to a conclusion that Parker will stay out of her business and not be so protective.
Parker, Watson and Osborn go out for one last meal before Osborn heads off to Europe. Parker thinks Osborn is hiding something from them and his reasons for going on the trip were vague.
Wilson Fisk and Norman Osborn meet up in a warehous, Fisk wants Osborn under his control and Osborn accepts by giving a list of requirements he wants for the relationship to work. Bingham is watching them.
Bingham reflects back to his past again, how the woman that had recruited him led him into a program where they took medicine often and how slowly the other patients there had died out. He recalls a guard and a patient who were cruel and had made fun of and absued the other patients so Bingham had killed them. The director of the facility was pleased with him though and upgraded his room.
Parker meets with Watson at the Daily Bugle and they figure out that Fisk killed Lopez's father and she is deaf as well as the fact that Fisk is trying to blackmail an Assistant District Attorney.
Spider-Man goes to the Assistant DA's apartment and finds out that there isn't enough blackmail to convince him, as well as him showing Spider-Man a clip of Norman Osborn praising Fisk.
Spider-Man goes to Andy's brother and finds out that he was lying about working with the Scorpion but that he had to instead do a job for someone. Watanabe calls and tells him that the assistant DA is dead and that there is webbing in his apartment, they figure out that Bingham has been used to distract them from Fisk. Echo is watching them and tells Jameson that Spider-Man has a connection inside the police department.
Fisk's security team informs him that Lopez has perhaps stolen something from one of his buildings.
Watson tells Parker that she is going to a fundraiser with Fisk and he tries to talk her out of it but this only irritates her.
Parker and Watanabe figure out that Fisk wants to be the Commissioner of Finance with help from Osborn.
Watanabe informs Parker that the fundraiser being held by Fisk is going to be hit by Tombstone, Watson will also be there and so Parker rings her and tells her not to go but she still wants to go anyway and seems excited. Spider-Man patrols the fundraiser and sees guns firing, he tries to stop people from getting hurt but the people who were firing were dressed as officers so Spider-Man realises his mistake. He goes out of the building and lands on the roof to which then he gets a call from the lab he works at and Peyton says he is fired for showing up late so often. Watanabe says they were set up and says they've got to take a hiatus from working with each other. Parker then goes to Watson's apartment to check on her, she breaks up with him, with his constant overshadowing of her life and telling not to pursue Fisk constantly, leads her to wanting her own space.
Over the next few months Parker becomes depressed but he still goes out as Spider-Man, and he put Scorpion and Electro into the Raft.
Watson cheers parker up and tells him to come up with new ideas so he decides to try and convince Echo that he didn't kill her father, he meets her on a rooftop and convinces her that Fisk killed her father, not Spider-Man. He does this via reasoning and files, she decides to help him.
Echo and Spider-Man infiltrate one of Fisk's buildings to steal a thumb drive that has the blackmail Fisk has on Osborn, however when they arrive there they find the safe empty and Fisk standing there with Bingham who names himself the Blood Spider. They fight and Spider-Man with Echo escape, however Blood Spider reveals he is actually working for Osborn and double crosses Fisk. It is revealed that Oscorp gave Blood Spider his powers.
At the event that will make Fisk Commissioner of Finance, Spider-Man fights Blood Spider for the thumb drive, he defeats him and Fisk gets escorted by Police and the thumb drive destroyed by Echo. Parker wants Echo to stay but she leaves to find some Cousins in Montana but before she leaves Echo gives Peter a file of dirt on Fisks operations, Parker gives it to Watanabe.
Months later Yuri Watanabe was promoted to Captain, Parker wasn’t fired from the lab, as Peyton didn’t have permission, so Peyton gets fired instead, J. Jonah Jameson switches his show to a podcast as to cut ties with Fisk and Parker and Watson hadn't spoken for a while. Leading directly into the first game, Peter wakes up to a police scanner alert about a raid on Fisk Tower.