In June 1969, severe weather looms on a rural Oklahoma farm. A family (including five-year-old Jo) seeks shelter in a storm cellar as an F5 tornado strikes. However, the storm is so strong that the locks on the cellar door fail and Jo's father is caught up in the storm and killed as young Jo struggles to catch a glimpse of the powerful storm.
Years later, Dr. Jo Harding is reunited with her estranged husband, Bill Harding . Bill is a former weather researcher and storm chaser who has taken a job as a weather reporter. He is planning to marry his new girlfriend, Dr. Melissa Reeves, and arrives at Jo's field station seeking Jo’s signature for the final divorce papers. Bill discovers that Jo has built four identical tornado research devices, all called DOROTHY, based upon his own design; the device is designed to release hundreds of sensors into the center of a tornado to study its structure. The team later meets up with Dr. Jonas Miller, a smug and unscrupulous (but well-funded) fellow meteorologist and storm chaser. When Bill discovers that Jonas has "invented" a device almost identical to DOROTHY, he vows to help Jo deploy DOROTHY before Miller can claim credit for the idea. Bill and Melissa join Jo and her eccentric team of storm chasers.
Tensions rise between Jo and Bill when they have several close calls with dangerous tornadoes as the team tries unsuccessfully to deploy the new device. During the first tornado, referred to in the commentary as an F-1, Jo's truck is tossed as the couple take shelter in a ditch. The truck and DOROTHY I are both destroyed. They continue chasing in Bill's truck, with Melissa in the back.
They find the second tornado, a stovepipe-shaped F-2, and head off on a backroad when it shifts its track. They soon find themselves driving through heavy rain. Before long the same storm drops onto a lake satellite tornadoes . Bill attempts to intercept them on a dam but is caught in the waterspouts, his truck being spun around until they dissipate.
Later, after a lunch with Jo's Aunt Meg, the chasers take off to chase yet another storm. As they track the storm they learn the tornado is on the ground, but have trouble finding it. Approaching a hill they run into a hailstorm, and Bill drives ahead of the chasers to intercept the oncoming pitch-black tornado (believed to be an F-3). A power pole falls on the back of Bill's truck and knocks DOROTHY II out onto the road, rendering it useless. As the tornado jumps and lands very close, Bill pulls an obsessed Jo into the truck and backs away to safety. The two have a meltdown between each other, involving their marriage and Jo's obsession with deploying DOROTHY into the tornado.
That night, a violent tornado blows away a drive-in movie theater, at which Bill and Jo's team is present. The F4 tornado later devastates Wakita, Oklahoma, destroying the home of Jo's aunt Meg. Melissa, frightened by the dangers of storm chasing and recognizing the unresolved feelings between Jo and Bill, leaves. After Bill and Jo rescue Aunt Meg, the scientists at NSSL report that an even stronger storm is forming 25 miles south of Wakita. As they predict that the storm could produce an F5 tornado, Jo realizes how to successfully deploy DOROTHY.
As the sun rises, the team attacks their goal with even more fervor, chasing a massive F5 tornado in an attempt to deploy the last two DOROTHY's. The rival team's hubris and lack of instinct proves fatal as Dr. Miller's truck is swept up and destroyed in the last tornado due to overzealous chasing, despite Bill's warnings. Eventually Jo and Bill set out on their own and, in a risky maneuver, are able to deploy the last DOROTHY successfully, surviving a direct contact with a huge F5 tornado and re-sealing their personal bond in the process.