In the thrilling finale of Marvel’s Spider-Man: The City That Never Sleeps, Silver Sable makes a striking return, determined to retrieve her stolen technology and equipment from Sable International, now in the hands of the city's criminals. With the police's Yuri Watanabe side-lined due to her controversial actions against the mobster Hammerhead, and facing even greater dangers ahead, Spider-Man finds himself uniting with unexpected partners to fend off looming disasters.

This concluding segment introduces new missions and adventures, spotlighting Silver Sable and her advanced hover-jet, besides a fresh series of encounters with the mischievous villain Screwball. Players are tasked with safeguarding the public against novel adversaries and addressing evolved criminal activities.