Not long after the Galactus catastrophe and the subsequent death of Captain America, the Ultimates disbanded, paving the way for Spider-Woman to form a new team without S.H.I.E.L.D. backing, focused on street-level criminal activities. She enlisted Miles, Kitty Pryde, Bombshell, and Cloak and Dagger, two other subjects of Roxxon's experiments. Together, the team battled the Serpent Skulls street gang led by rogue S.H.I.E.L.D. agent Brock Rumlow, AKA Crossbones. Their team wasn't trusted or respected due to their youth and relative inexperience, but after taking on Scourge, a serial killer who hunted criminals, they were able to gain the trust of the local law enforcement.
When the time-displaced X-Men from the prime timeline arrived in this reality, Spider-Man introduced them to his reality's X-Men. After battling Doctor Doom, he also helped them get home. Spider-Man and Black Widow were then embroiled in a reality-spanning war when the Inheritors, a group that feasted on spider powered people, attacked them. Spider-Man and Black Widow joined with other alternate-reality Spider-Men and Women to defeat the Inheritors. With this reality's S.H.I.E.L.D. gone following Galactus' attack, custody of a S.H.I.E.L.D. prison facility was transferred to the private sector. With the loosened security, Green Goblin, previously thought dead, easily escaped.
Meanwhile, Miles prepared to tell his girlfriend, Katie, that he was Spider-Man. Asking Mary Jane Watson for advice, Miles learned that Peter Parker was still alive and secretly living a normal life. Miles told Katie his secret, but she ran away in fear. The Green Goblin soon attacked Miles, angry someone else was Spider-Man, but Peter joined Miles in driving off the villain. As the Spider-Men regrouped, Osborn apparently murdered J. Jonah Jameson. Then Green Goblin attacked again, and in their rage, the Spider-Men apparently killed him. Peter then gave Miles his blessing to continue being Spider-Man before leaving with Mary Jane. That night, after a change of heart, Miles' dad returned home and reconnected with his son. Miles went to Katie's home to straighten out their relationship, but Katie's father attacked him, revealing himself as a Hydra agent and his family as Hydra members, including Katie. Hydra abducted Miles' family and friends and, with Doctor Doom's help, prepared to experiment on Miles to reverse engineer his spider powers.
When Doom's tests accidentally triggered an explosive release of Miles' venom blast ability, Miles broke free. Simultaneously, the Ultimates tracked down Miles and helped him defeat Doctor Doom. As Miles ended his relationship with Katie, the prime universe appeared in the middle of nearby space, turning the sky red, signaling an incursion between Earths during the collapse of the Multiverse. During a battle between the two Earths, Spider-Man hid aboard a life raft carrying the Cabal, a group of nihilistic beings who had slaughtered worlds in trying to stop the Multiverse's collapse. Surviving reality's destruction in the raft, Spider-Man eventually found himself on Battleworld, a planet created from reality's remnants by an all-powerful Victor von Doom of the prime reality, eventually encountering the Manhattan realm comprised of fragments of both realities.