In the heart of the Amazon jungles of Peru in 1973, a dedicated research team, led by Ezekiel Sims and his pregnant colleague Cassandra Webb, makes a groundbreaking discovery of an unidentified spider species known for its remarkable healing qualities. While Cassandra focuses on the potential medical applications of the spider's venom to cure various ailments, Ezekiel's interests lean towards the prospect of achieving superhuman strength from it. After a challenging quest through the treacherous jungles, Cassandra triumphantly locates the creature she has been seeking. However, in a shocking turn of events, Ezekiel betrays the team during a struggle for the spider, resulting in him shooting Cassandra and leaving her to perish alone. Although a local tribe attempts to save her by having the spider bite her, she tragically dies shortly after giving birth to Cassandra (Dakota Johnson).
Fast forward thirty years, we find Cassandra, now affectionately known as "Cassie," living in New York City and working as a paramedic alongside her coworkers Ben Parker and O'Neil. Orphaned as a child, Cassie harbors her mother’s research notes in a suitcase, remnants of the past that she doesn’t truly understand. During a perilous emergency call involving a flipped car, she falls into the water and has a near-death experience. With the quick actions of Ben, she is revived but starts experiencing eerie visions that she initially brushes off as simple déjà vu.
As fate would have it, the unit responds to a fire at an industrial facility, leading Cassie to envision a tragic scene in which she fails to save O'Neil. This ghastly vision ultimately comes true, resulting in O'Neil's untimely death. Faced with this sorrowful reality, she realizes she possesses the uncanny ability to foresee events that lie ahead.
Meanwhile, Ezekiel, now enhanced with limited precognitive abilities, is on the hunt for three teenage girls—Julia Cornwall, Anya Corazón, and Mattie Franklin—whom he believes are destined to become Spider-Woman and threaten his life. Using National Security Agency tools and a hacker, he tracks the girls down with a singular intent of eliminating them before they can fulfill this perceived fate.
As the paths of Cassie and the girls eerily intertwine, they congregate one fateful day in a train carriage, where Cassie senses that danger lurks. Realizing the imminent threat posed by Ezekiel, she takes decisive action to safeguard them. In a dramatic confrontation at Grand Central Terminal, Ezekiel, clad in a black Spider-Man suit, launches an attack, showcasing his agility and ability to evade bullets. Cassie quickly commandeers a taxi, escaping the city with the girls to the safety of a nearby forest, where they bond over their past encounters.
Returning to her apartment, Cassie pores over her mother’s notes, unraveling the enigma of Ezekiel's powers, which are linked to the venomous spiders. In a revealing moment, she discovers that her mother never sought the spider's power for selfish reasons, but rather to protect her daughter from a hereditary disease. When the girls recklessly venture out to a diner, which leads to their discovery by Ezekiel, it becomes a race against time for Cassie to rescue them.
In a thrilling chase back to Queens to evade capture, they seek refuge in Ben’s home. Overwhelmed, the girls realize Cassie is their only hope. As pressure mounts, Ezekiel's connection to Cassie is unveiled, and it becomes clear he believes he must extinguish the girls to secure his survival. Cassie learns of the neurotoxin Ezekiel’s hands release, prompting her to teach the girls crucial life-saving techniques.
Desperate to confront her past, Cassie takes a perilous journey back to Peru to discover the truth from the tribal chief who saved her mother. Undergoing a transformative ritual, she encounters a higher plane of existence that reveals the fundamental interconnectedness of all life. In the climax, as Mary, played by Emma Roberts, unexpectedly goes into labor, Cassie orchestrates a daring plan to lure Ezekiel to a familiar site, setting a trap for him while ensuring Mary and the girls remain safe.
In a heart-stopping confrontation that leads to Ezekiel's downfall, Cassie emerges as a hero but suffers grievous injuries that leave her blind and paraplegic. Yet, her newfound clairvoyance unlocks unprecedented visions of the future. Assured of her purpose, she vows to mentor the girls, setting the stage for their future as potential defenders against evil.
