In 1973 in the Amazon jungles of Peru, a research team led by Ezekiel Sims (Tahar Rahim) and his pregnant colleague Constance Webb (Kerry Bishe) discovers an unidentified species of spider with rare healing properties. Ezekiel is providing security for the mission, while Constance leads the mission. Constance says that the Peptides in the spider's venom supercharge their cellular structure. Constance says that these spiders have the potential to cure hundreds of diseases, while Sims is more interested to see if the spiders can give superhuman strength. After an arduous search, and battling pain, Constance finds the spider she is looking for. Ezekiel betrays the team and claims the spider for himself, shooting Constance in a struggle over the spider before leaving her for dead. An indigenous tribe attempts to save Constance by having the spider bite her, but she dies shortly after giving birth to Cassandra (Dakota Johnson).
Thirty years later, Cassandra, going by "Cassie", works as a paramedic in New York City alongside her co-workers Ben Parker (Adam Scott) and O'Neil (Mike Epps). Cassandra was raised as a foster kid. In her suitcase at home, Cassandra has Constance's notes from her research. During a dangerous call (a flipped over car on a bridge), Cassie falls into the water and has a near-death experience. Ben revives her, but she begins to experience visions. Initially, she dismisses them as Deja Vu, but then the unit is called to a fire in an industrial complex packed with explosives. Cassandra has a vision where she is trying to revive O'Neill's dead body. She fails to act, which results in O'Neill driving away in the ambulance and being struck down by a semi-truck. The accident ends up killing O'Neill. After failing to prevent O'Neil's death, Cassie realizes that she can see into the future. Cassie also finds that by acting timely she has the opportunity to act on her visions and prevent specific events from taking place in the near future.
Ezekiel, who has limited precognition power and enhanced physical abilities, collects information on three teenage girls: Julia Cornwall (Sydney Sweeney) (An awkward teenage girl who lives with her father and stepmother following her mother's departure), Anya Corazon (Isabela Merced) (A teenager forced to live alone after her father's deportation), and Mattie Franklin (Celeste O'Connor) (A teenage girl from a wealthy family, but with absent parents). His visions lead him to believe that the 3 girls will turn into Spider-Woman, and that they are destined to kill him at some point in the near future. Sims seduces a National Security Agency (NSA) (Jill Hennessy) agent and used the NSA facial recognition software to find the 3 girls from his visions.
Sims works with a hacker who extracts the images of the 3 girls from his dreams and then runs them by the NSA software to track them down. The hacker tracks down all 3 girls at the Grand Central Station. Cassie and the 3 girls enter the same train carriage, and Cassie has visions of them being attacked by Sims. Cassie is drawn to the girls and intervenes to stop Ezekiel from ambushing them at Grand Central Terminal. Sims is in a black Spider-man costume and attacks the cops when Cassie tries to hide with the girls behind them. Sims is able to climb walls and dodge bullets.
Cassie steals a taxi and takes Julia, Anya, and Mattie out of the city to hide them in a nearby forest (when she finds on radio that she is suspected to be the attacker and kidnapper of the 3 girls). In the forest, Cassie and the girls realize that they have all crossed paths earlier as well. Cassie reveals that she has the power to see the future. Cassie returns to her apartment and finds Constance's notes, which reveal Ezekiel's identity and the true nature of his powers. She finds that the Spider People derive their powers from spider venom and are very fast and strong. They can climb like spiders. They also have a sixth sense, like the ability to glimpse the future. She finds a photo of Sims with Constance in her diary.
Ignoring Cassie's instructions, the girls go to a diner where Ezekiel finds them through the NSA software (a diner recognizes the missing girls and calls 911, and the call is tracked by the hacker working for Sims). Cassie returns to the forest and finds the girls missing. She has a vision of them being attacked by Sims. After briefly incapacitating Ezekiel by ramming him with the car, Cassie takes the girls back to Queens and they take refuge in Ben's house. The girls are now convinced that only Cassie can save them and somehow, they need to get to the bottom of the mystery. Sims realizes that Cassie is the daughter of Constance.
Cassie again has a vision where Sims explains that he needs to kill the girls as in the future he has seen them destroy him. Cassie realizes that Sims hands release a Neurotoxin which can be fatal to humans if enough of it gets into your system. The cardiac arrest can be offset by CPR, which she teaches to the girls.
Cassie flies to Peru and tracks down the tribal chief Santiago (José MarÃa Yazpik) who saved her mother. The chief puts Cassie through a ritual that separates her soul from her body. She experiences a plane of higher consciousness where all living things are connected and where every possible future can be seen. She learns that Constance sought the spider not for fame or money, as she had originally thought, but to save her from having the same fatal hereditary disease that Constance suffered from. In fact, Constance put her own life and comfort in danger, so she could save Cassie, as that is how much she loved her.
Ben's pregnant sister-in-law Mary (Emma Roberts) goes into labor earlier than expected and he takes her to the hospital, along with the girls, who are seen on camera when in the car. Ezekiel intercepts them again, but Cassie rescues the girls in an ambulance and distracts Ezekiel so Ben and Mary can escape. The group lures Ezekiel to a condemned firework factory (the same site which was engulfed in fire earlier and where O'Neil met his death) and sets up traps to disorient him while Cassie calls for a medical evacuation helicopter to fly to their location. Ezekiel destroys the helicopter and separates the girls, then taunts Cassie with Constance's death.
Cassie uses her supernatural powers (with her soul separating from her body to help the girls) to guide the girls to safety. She sets off the final trap, which fatally crushes Ezekiel. An ignited firework strikes Cassie in the face, blinding her. Cassie is taken to the hospital just as Mary gives birth to her son. Cassie wakes up to discover that she is now blind and paraplegic due to her injuries. However, her clairvoyance enables her to see fully into the future. Cassie assures the girls that she will mentor them in their future roles when the time comes.
