Tom Holland's Spider-Man has always prided himself for being morally sound, and it has proved to be a major downfall for his character. In his wish to be a hero that operates only on the right side of the line, he has been forced to compromise that on more than one occasion. That guilt is what provides a link between two of the web-slinging hero's most formidable opponents.
In Holland's own films, he has faced Vulture (Michael Keaton) and Mysterio (Jake Gyllenhaal). His third film, Spider-Man: No Way Home will feature a number of Spider-Man villains including ones from Tobey Maguire and Andrew Garfield's films. Among them is Willem Dafoe's Green Goblin who will likely remind Holland's Spider-Man of some of the guilt he is still carrying around.
Spider-Man: Far From Home was an emotionally heavy film because of Peter's recent loss of his mentor, Iron Man. Thinking he may have finally found someone else to trust, Peter gifted E.D.I.T.H. to Mysterio, only to discover he made a huge mistake. He is then forced to try and correct this error by defeating Mysterio but even this doesn't go according to plan. Mysterio attempts to use optical illusions to further trick Peter, but his methods eventually run dry. Mysterio is shot by one of his own drones and seemingly dies not long after. While Mysterio's death isn't directly by the hands of Spider-Man, Peter still holds himself responsible for not being able to save him. For him, even those that have committed some of the world's most ultimate betrayals, don't deserve to die for what they've done.
Mysterio's death is similar to Green Goblin's in Maguire's first Spider-Man film. Green Goblin dies shortly after unveiling his true identity to Peter, in hopes that it will allow him to drop his guard enough for the Green Gobin to kill him. He calls for his glider which Spider-Man quickly avoids. Unfortunately, Green Goblin's reaction time isn't as quick and he is impaled by his own glider. After learning that the true identity of Green Goblin is Norman Osborn, Maguire's Spider-Man becomes conflicted much like Holland's Spider-Man after Mysterio's death. Maguire's Peter adored Norman Osborn and while he was the man beneath the Green Goblin attire, the death of Green Goblin meant the death of Norman. This complicated things for Maguire's Peter in many ways, including his relationship with his best friend Harry Osborn.
Other Spider-Man villains have also died in circumstances that are not directly by Spider-Man's hand. In Spider-Man 2, Doc Ock sacrificed himself in order to destroy his experiment. In Garfield's Amazing Spider-Man 2, Electro is electrocuted and therefore defeated. Even Vulture is defeated by his own invention in Spider-Man: Homecoming, even though he doesn't die. Green Goblin and Mysterio just happen to be opponents that hold an emotional weight for their respective Spider-Men. Garfield may not have a villain that evokes a similar emotion, but he does have a score to settle with Green Goblin.
With Green Goblin appearing in No Way Home, his presence may remind Holland's Spider-Man of what happened with Mysterio. Holland's Spider-Man may not have met Green Goblin before, but much like Doc Ock in the second No Way Home trailer, Green Goblin may notice that Holland isn't the same Peter that previously defeated him. If Maguire appears in No Way Home and relays the history between himself and Green Goblin, it will likely trigger the emotions Holland had with Mysterio. It was a man he trusted and confided in that betrayed him deliberately. The same could be argued for Green Goblin and Maguire's relationship.
If Holland does begin to reminisce on what happened with Mysterio, the guilt he feels will likely impact his response to the new group of villains he will confront. In Spider-Man: Homecoming, Vulture was imprisoned and is known to still be alive. Doc Ock is shown to be captured and held hostage in No Way Home, and that fate is likely the ideal choice for Holland's Spider-Man. In Spider-Man: Homecoming, Peter tried to acclimate himself with the new Spider-Man suit that was gifted to him by Tony Stark, and one of its features was an instant kill mode. Peter protested the use of this adamantly and only ended up using it to help the Avengers in the fight against Thanos.
With the perception of Holland's Spider-Man already being questioned in No Way Home now that Mysterio has outed his identity and subsequently labeled him as a murderer, circumstances for him have severely changed. Now that the world is beginning to turn against him, Peter's feelings for himself will likely fluctuate. Feeling that he must isolate himself from those he loves in order to protect them will probably only continue to impact his mental and emotional health. Holland has already gone on record to call No Way Home "sad" and "dark," meaning that whatever his character faces will change the course of Spider-Man for years to come.
Spider-Man: No Way Home releases in theaters on December 17, 2021.