Kate Dibiasky, a doctoral candidate in astronomy at Michigan State University, discovers an unknown comet. Her professor, Doctor Randall Mindy, confirms that it will collide with Earth in approximately six months and is large enough to cause a global extinction event. NASA verifies the findings, and Dr. Teddy Oglethorpe, head of their Planetary Defense Coordination Office, accompanies Dibiasky and Mindy to present their findings to the White House. However, they are met with apathy from President Janie Orlean and her Chief of Staff Jason Orlean, who is also her son.
Oglethorpe encourages Dibiasky and Mindy to leak the news to the media, which they do so on The Daily Rip, a popular morning talk show. When hosts Jack Bremmer and Brie Evantee treat the topic lightly, Dibiasky loses her composure and angrily rants about the threat. Mindy receives public approval for his looks, while Dibiasky becomes the subject of negative memes for her on-air behavior. Actual news about the comet's threat receives little public attention, and the danger is denied by Orlean's NASA Director Jocelyn Calder, a top donor to Orlean with no background in astronomy. When news of Orlean's sex scandal with her Supreme Court nominee Sheriff Conlon is exposed, she distracts from the bad publicity by finally confirming the threat and announcing a project to strike and divert the comet using nuclear weapons.
The mission successfully launches, but Orlean abruptly aborts it when Peter Isherwell, the billionaire CEO of BASH Cellular and another top donor, discovers that the comet contains trillions of dollars worth of rare-earth elements. The White House agrees to commercially exploit the comet by fragmenting and recovering it from the ocean, using technology proposed by BASH in a scheme that has not undergone peer review. Orlean sidelines Dibiasky and Oglethorpe while hiring Mindy as the National Science Advisor. Dibiasky attempts to mobilize public opposition to the scheme but gives up under threat from Orlean's administration. Mindy becomes a prominent voice advocating for the comet's commercial opportunities and begins an affair with Evantee.
World opinion is divided among people who believe the comet is a severe threat, those who decry alarmism and believe that mining a destroyed comet will create jobs, and those who deny that the comet even exists. When Dibiasky returns home to Illinois, her parents kick her out of the house and she begins a relationship with a young man named Yule, a shoplifter she meets at her retail job. After Mindy's wife confronts him about his infidelity, she returns to Michigan without him. Mindy questions whether Isherwell's technology will be able to break apart the comet, angering the billionaire. Becoming frustrated with the administration, Mindy finally rants on national television, criticizing Orlean for downplaying the impending apocalypse and questioning humanity's indifference.
Cut off from the administration, Mindy reconciles with Dibiasky as the comet becomes visible from Earth. Mindy, Dibiasky, and Oglethorpe organize a protest campaign on social media, telling people to "Just Look Up" and call on other countries to conduct comet interception operations. Simultaneously, Orlean starts an anti-campaign telling people "Don't Look Up". Orlean and BASH cut Russia, India, and China out of the rights for the comet-mining deal, so they prepare their own joint deflection mission, only for their spacecraft to explode. As the comet becomes larger in the sky, Orlean's supporters start turning on her administration. BASH's attempt at breaking the comet apart goes awry, and everyone realizes that humanity is doomed.
Isherwell, Orlean, and others in their elite circle board a sleeper spaceship designed to find an Earth-like planet, inadvertently leaving Jason behind. Orlean offers Mindy two places on the ship, but he declines, choosing to spend a final evening with his friends and family. As expected, the comet strikes off the coast of Chile, causing a worldwide disaster and triggering an extinction-level event. The shockwave strikes Mindy's house, killing everyone inside.
In a mid-credits scene, the 2,000 people who left Earth before the comet's impact land on a lush alien planet 22,740 years later, ending their period of suspended animation. They exit their spacecraft naked and admire the habitable world; however, Orlean is suddenly killed by a bird-like predator, one of a pack that surrounds the planetary newcomers.
In a post-credits scene back on Earth, it is revealed that Jason managed to survive the impact. He records himself, declaring himself the "last man on Earth" and asking any viewers to "like and subscribe".
