Brian and the Eeveelution Family's Adventures of Spider-Man 3 is is the third and final upcoming Family Guy/Pokémon/Spider-Man crossover to be made by Hiatt Grey. And it is the sequel to Brian and the Eeveelution Family's Adventures of Spider-Man 2.
Peter Parker plans to propose to Mary Jane Watson, who has just made her Broadway musical debut. A meteorite lands near the two at Central Park, and an extraterrestrial symbiote follows Peter to his apartment. Meanwhile, police pursue escaped prisoner and robber Flint Marko, who visits his wife and sick daughter. The chase resumes, and Marko falls into an experimental particle accelerator that fuses his body with the surrounding sand, transforming him into Sandman. Harry Osborn, seeking vengeance for his father's death, attacks Peter with new weapons based on his father's Green Goblin technology. The fight results in Harry receiving amnesia, erasing his memory of Peter as Spider-Man as well as his vengeance.
During a festival honoring Spider-Man, Peter kisses Gwen Stacy for show, infuriating Mary Jane. A newly superpowered Marko robs an armored car and Spider-Man confronts him. Initially warning him to leave to avoid a fight, Marko easily subdues him and escapes. NYPD Captain George Stacy tells Peter and Aunt May that Marko was Uncle Ben's true killer; the deceased Dennis Carradine was Marko's accomplice. While a vengeance-obsessed Peter sleeps in his Spider-Man costume, the symbiote assimilates his suit. Peter wakes up hanging from a skyscraper, discovering his costume changed and his powers enhanced, but the symbiote brings out Peter's dark side. Wearing the new suit, Spider-Man locates Marko and battles him in a subway tunnel, the symbiote influencing him to fight more brutally. He discovers water is Marko's weakness and breaks a water pipe to reduce Marko to mud, washing him away and believing him dead.
Peter's changed personality alienates Mary Jane, whose career is floundering, and she finds solace with Harry. Harry recovers from his amnesia, and urged by a hallucination of his father, threatens Mary Jane into breaking up with Peter. After Mary Jane tells Peter she loves somebody else, Harry meets with Peter and claims to be "the other guy". Later, Peter, wearing the black suit, confronts Harry, and spitefully tells him his father never loved him. After a violent fight, Harry throws a pumpkin bomb at Peter, who deflects it back, disfiguring Harry's face.
Under the symbiote's influence, Peter exposes photography rival Eddie Brock by proving his fake photos depicting Spider-Man as a criminal. Soon afterward, to make Mary Jane jealous, Peter brings Gwen to the nightclub where Mary Jane now works, but Gwen catches on and leaves. Peter brawls with the bouncers and, after accidentally attacking Mary Jane, realizes the symbiote is corrupting him. Retreating to a church bell tower, he discovers he cannot remove the suit, but the symbiote weakens when the bell rings. Peter removes the symbiote and it falls to the lower tower, landing on Brock, who had been praying for Peter's death. The symbiote bonds to Brock's body, transforming him into Venom. Brock finds Marko and convinces him to join forces to defeat Spider-Man.
Brock hijacks Mary Jane's taxi and hangs it as bait from a web above a construction site while Marko keeps the police at bay. Peter seeks Harry's help, but is rejected. While Peter battles Brock and Marko, Harry learns the truth about his father's death from his butler, and goes to help Peter as he is being overpowered, resulting in a battle between the four. Harry subdues the Sandman before assisting Peter against Brock. In the ensuing confrontation, Brock attempts to impale Peter on Harry's glider but Harry intervenes and is mortally wounded. Recalling the symbiote's weakness, Peter uses metal pipes to create a sonic attack, weakening Venom and allowing Peter to separate Brock and the symbiote. Peter activates a pumpkin bomb from Harry's glider to destroy the symbiote but Brock dives in and the bomb kills them both.
Marko explains to Peter that he committed robberies to save his dying daughter and reveals that while Ben was convincing Marko to go home after getting him out of his car, Carradine hit Marko's elbow, shooting Ben accidentally, plaguing Marko with guilt. Peter forgives Marko, who dissipates and floats away. Peter rejoins Mary Jane and Harry. The two reconcile as Harry dies beside them. Peter, MJ and Aunt May attend Harry's funeral. Later at the nightclub, Peter and Mary Jane reconcile their relationship.
- The Griffin Family, Glenn Quagmire, Cleveland Brown, Joe Swanson, Little Bear, Duck, Cat, Owl, Hen, Emily, Lucy, Pazu, Sheeta, and The Crystal Prep Girls guest star in this film.
- Ernie the Giant Chicken and The Dazzlings will work for Venom in this film.
- The end credit song will be "Signal Fire" performed by Snow Patrol just like from the actual movie.