In June 1969, in western Oklahoma, 5-year old Jo Thornton and her family are awakened by an approaching F5 tornado. The family seeks refuge in their storm cellar, but while attempting to hold it down, the tornado rips the cellar door off and pulls Jo’s father to his death inside the vortex.
27 years later, Jo has become a meteorologist and storm chaser on the trail of a predicted record outbreak of tornadoes in Oklahoma. Jo is reunited with her estranged husband, Bill Harding (Paxton), a former weather researcher and fellow storm chaser turned television weather reporter, who is planning to marry reproductive therapist Melissa Reeves (Gertz). Visiting Jo’s camp to get her to complete the divorce forms, Bill finds that she and her team have built four tornado research devices called DOROTHY based on his design. Each unit contains hundreds of sensors that, if picked up by a tornado, will provide data that could lead to breakthroughs in meteorological research and improve the lead time for tornado warnings in advance of a tornado’s arrival. Before Jo can finish the paperwork, her team rushes to intercept an F1 tornado forming nearby, forcing Bill and Melissa to chase after her. Bill encounters Dr. Jonas Miller (Elwes), a corporate-funded meteorologist and long-time rival storm chaser, and learns that he has created a device called DOT-3 (Digital Orthographic Telemeter), a blatant copy of DOROTHY. Bill vows to help Jo deploy DOROTHY before Jonas can deploy DOT-3 and claim credit for the idea.
In an attempt to deploy DOROTHY, Bill maneuvers Jo’s Jeep Gladiator off-road into a muddy ditch towards the rapidly growing tornado. They collide with a small wooden bridge and find themselves trapped in the direct path of the oncoming tornado. As they take cover underneath the bridge, Jo’s truck and DOROTHY I are both picked up and destroyed by the tornado.
A second tornado is spotted. Jonas and his team are also moving to intercept the tornado, which has strengthened to F2 intensity. However, Bill’s intuition that the tornado will shift its path sends them off seemingly in the right direction. Bill, Jo, and Melissa have a dangerous encounter with twin waterspouts on a enclosed road and are spun round by the sideswiping tornadoes, leaving Melissa shaken. The rest of the team, however, is ecstatic about the encounter and convince Jo to let them go visit her aunt, Meg (Lois Smith), in the nearby town of Wakita for food and rest.
While there, the team informs Melissa about Jo’s backstory, explaining that Jo has since become obsessed with ensuring nobody else suffers the same fate as her father. Jo, realizing she is falling in love with Bill again, isolates herself from the rest of the group and is confronted by Aunt Meg, who tells her that no matter what happens, they will always end up together.
They learn an F3 tornado is quickly forming in a neighboring county. As the team attempts to intercept the F3, the tornado initially fails to appear. They make yet another attempt to deploy a DOROTHY unit, but the tornado forms perilously close to them, toppling an electrical pole onto DOROTHY II, hitched on the back of the truck, destroying it. Overwhelmed by these recent events and racked with guilt over her father’s death, Jo begins to despair. As their emotions run high, Bill tells Jo that he’s still in love with her, unaware that Melissa is hearing the conversation over CB radio.
That night, the team stays in a hotel next to a drive-in cinema that is showing The Shining. Jo decides to fill out the remaining divorce papers, but is interrupted when an F4 tornado approaches, forcing her team as well as townspeople caught in the storm to take shelter. Finding herself traumatized by the recent near-death experiences and recognizing the re-blossoming love between Bill and Jo, Melissa peacefully ends her relationship with Bill and makes her own way home. The tornado continues on to devastate Wakita; upon the team’s arrival in the town, Jo and Bill rescue an injured Aunt Meg from her flattened home before the destabilized second floor collapses. As Meg is about to be taken to a nearby hospital and chase team member Dusty (Philip Seymour Hoffman) informs Jo that the team has heard that an F5 is forming close by, Meg pushes Jo not to give up, reminding her that Wakita had been hit by the tornado essentially without warning, the tornado sirens having barely gone off before it struck. In a brief moment of quiet, Jo absently watches Aunt Meg’s wind chimes. The image inspires an epiphany and she begins to form a plan to improve and deploy the next DOROTHY unit.
As the sun rises, the team sets out to intercept the F5 tornado, which has grown to be over a mile (nearly 2 km) wide. Bill and Jo lay the newly altered DOROTHY III directly in the F5’s path, but it is destroyed by an uprooted tree. Meanwhile, Jonas attempts to deploy DOT-3 in a similar fashion, ignoring Bill’s repeated warnings that his team is too close and that the tornado is shifting directly towards them. A metal tower impales Jonas’ driver, Eddie (Zach Grenier), and their vehicle is swept into the tornado and thrown to the ground, killing both men and destroying DOT-3 in the resulting explosion. Bill and Jo press on, realizing that the only way to successfully deploy DOROTHY IV is by driving directly into the tornado and jumping out before Bill’s truck is swept away. The plan works and the rest of the team celebrates the successful deployment of DOROTHY IV. However, Bill and Jo’s celebration is cut short when the F5 shifts direction towards them. They flee into the nearby cornfields and take shelter in a water pump facility, fastening themselves to deeply rooted pipes. As the tornado passes overhead, they are able to see the tornado’s interior, before the storm dissipates altogether. The rest of the team arrives on scene to celebrate the achievement while Jo and Bill excitedly plan the next phase of research, deciding to run their own lab and rekindle their marriage.