The full story
In 1973, in the Amazon rainforest, pregnant researcher Constance Webb leads an expedition studying a rare spider whose venom carries extraordinary healing properties—she is hoping it can cure the congenital disease already diagnosed in the daughter she is carrying. Ezekiel Sims, hired as protection for the expedition, decides he wants the spider's power for himself, shoots Constance, and steals it. As she is dying, the tribe that discovered the spider has one bite her in a last attempt to save her; it isn't enough to save her life, but it passes the spider's properties to the daughter she delivers as she dies: Cassandra.
Thirty years later, Cassie Webb is a paramedic working the streets of New York with her partner Ben Parker. Responding to a call, she nearly drowns; Ben resuscitates her, and she wakes with the ability to glimpse a few seconds of the future before snapping back to the present with time left to act on what she saw.
Cassie's visions lead her to Ezekiel Sims, now decades into a life built around the same spider-given power: precognition and enhanced strength. His own visions show three teenagers—Julia Cornwall, Anya Corazon, and Mattie Franklin—growing into Spider-Women who kill him. He has never met them, and intends to make sure that future never happens.
Cassie's visions put her a step ahead of Ezekiel across the city—including pulling one of the three clear of danger on a subway car—before confronting him directly at Grand Central Terminal. She gets Julia, Anya and Mattie out of Manhattan, first to a forest outside the city, then to the Queens home of her partner Ben and his pregnant sister-in-law, Mary Parker.
While Ezekiel closes in, Cassie travels to Peru to learn more about her mother's research and her own power. A ritual with Santiago, the tribal chief who tried to save her mother decades earlier, sharpens her clairvoyance into something closer to control—a vision of a plane where every possible future can be seen.
Cassie leads Julia, Anya and Mattie to a condemned fireworks factory, rigging it with traps ahead of Ezekiel's arrival and using her foresight to know exactly where he'll be at each step. The plan works: Ezekiel is crushed by the final trap. A firework ignited in the same struggle badly injures Cassie.
Cassie survives, but the injury leaves her blind and unable to walk; her clairvoyance, if anything, sharpens further. She commits to mentoring Julia, Anya and Mattie as they grow into the Spider-Women her visions first showed her. Back in Queens, Mary Parker goes into labor as the film ends; her and Ben's newborn nephew is never named on screen, but it's Peter Parker.
Madame Web has no mid-credits or post-credits scene—the only entry in Sony's Spider-Man Universe without one. Director S.J. Clarkson has said the choice was deliberate: the story had already reached its ending.