The film opens at a space station where PHD candidate Kate Dibiasky (Jennifer Lawrence) spots what looks like a comet hurtling towards Earth. She calls in her colleagues to celebrate, including her mentor, Professor Randall Mindy (Leonardo DiCaprio). However, the two soon notice that the comet is far more dangerous than they had anticipated based off the readings they are picking up.

Randall and Kate get in touch with several official figures, including Dr. Teddy Oglethorpe (Rob Morgan), to get the word out that the comet is a “planet killer”, and in six months time, it will effectively destroy all life on the planet. They attempt to secure a meeting with President Janie Orlean (Meryl Streep), though the stress of it makes Kate vomit and resort to getting high to cope with her stress.

After an unsuccessful night of waiting for Janie’s time to free up, Randall, Kate, and Teddy have to wait until the next day to break the news to Janie and her Chief-in-Staff son Jason (Jonah Hill). Despite Randall and Kate playing up the major imminent threat, Janie and Jason don’t seem to care much for it and don’t think of it as a legitimate threat since their statistics are not at 100% certainty. Because of this, they will not play up the threat of the comet, which Randall has dubbed “Comet Dibiasky” since Kate first noticed it, and don’t view it as a big deal.

Kate is seen communicating with her boyfriend, Phillip (Himesh Patel), with whom she has somewhat of a strained relationship since she doesn’t want to spend time with his mother, while Randall is married to June (Melanie Lynskey), and they have two adult sons who live at home.

In Silicon Valley, there is a presentation by big tech company Bash, with CEO Peter Isherwell is unveiling the newest update to his company, Liif, which detects how people are feeling and works to appeal to them as it works in the favor of the company so they can sell their stuff. Peter is also shown to be a callous jerk.

Randall and Kate manage to score an interview with major television personalities Brie Evantee (Cate Blanchett) and Jack Bremmer (Tyler Perry). Before they go on to break the comet story, pop star Riley Bina (Ariana Grande) is up to talk about her highly publicized breakup with fellow musician DJ Cello (Scott Mescudi). The two have a live chat where they reconcile, and Riley accepts Cello’s marriage proposal. Afterward, Randall and Kate go on air, with Randall managing to maintain his composure, but Kate loses her cool due to Brie and Jack’s nonchalance at the situation, and Kate loudly declares to the viewers that they will all “fucking die”.

Following the disastrous interview, Kate becomes a meme due to her doomsday cries bumming people out, while Randall becomes popular because of his looks. The two return home.

FBI agents soon arrest Randall and Kate and bring them to the White House to meet with Janie. After she has been caught in some kind of scandal, it becomes clear that she wants to use the comet to divert attention away from that issue onto this one. She agrees to go through with a mission where decorated war hero Benedict Drask (Ron Perlman) will head a team outside of Earth’s atmosphere to nuke the comet. As word of the comet’s impact and the big mission comes out, Randall begins an affair with Brie since he becomes a recurring guest on the show.

The nation watches as Benedict and his team are launched into space in the face of the comet. While in the briefing room where Janie meets with Randall, Kate, Brie, Teddy, and other officials, Peter calls Janie out to tell her something. Moments later, Benedict and his team appear to be retreating from space and begin pulling back toward Earth, effectively aborting the mission.

Randall and Kate later meet with Janie and her staff since Peter had determined based on his readings that the comet can provide a great source of wealth and material for the big companies like his own to fuel their products and services, so they are willing to let the comet strike in order to profit off of it. Randall and Kate are both mortified, but Randall becomes sucked into the media circus and becomes a puppet for Bash and the other pro-comet businesses that believe they can profit from the comet. Soon, several factions across the country start to swing in favor of the comet because they think it can provide jobs for the needy, while those arguing to stop the comet are seen as the bad guys. Even Kate’s parents don’t want to deal with her because they are pro-comet.

Randall continues working with the Orlean administration, as well as his affair with Brie, while Kate takes a job at a supermarket and later hooks up with an anti-government activist named Yule (Timothe√© Chalamet). June later confronts Randall and Brie for their affair and throws all of his numerous medications at him. After Randall sees that Peter is trying to use Bash drones to mine the comet, he starts to have a change of heart. It culminates with him having a full-on meltdown on Brie and Jack’s show, criticizing the Orlean administration, as well as the public’s whole reaction to the ordeal. He gets a bag on his head like Kate did when she was apprehended by the FBI, and Brie breaks things off with Randall.

Soon, the comet starts to come into Earth’s atmosphere. Kate reconciles with Randall and rejoins him, along with Yule. Once the rest of the planet becomes aware of the comet, stupid internet trends like the “Launch Challenge” become viral, while people on both sides of the political spectrum attempt to capitalize on the frenzy. A movie starring actor Devin Peters (Chris Evans) also goes into development. Janie and her administration go against Randall’s warnings about “Don’t Look Up” and host a concert with Riley and Cello performing a ballad called “Just Look Up”. While Randall and Kate attempt to gather help from other nations, Janie and her staff pull funding from countries like India, Russia, and China so that they can go ahead and continue their mining mission.

With little time left, and with zero chance of fighting things, Randall gathers with his family, as well as Kate, Teddy, and Yule to share a final meal together with good company. The drones sent to mine the comet begin to falter or get destroyed, and both Janie and Peter realize their efforts are futile. Janie calls Randall and tells him that there is room for him and a guest on a shuttle where all the rich folks are gathering to avoid the impact of the comet in cryopods. Randall declines and chooses to stay with his loved ones, although it becomes evident that Janie forgot Jason and is leaving him to his doom. The comet soon clears Earth’s atmosphere and hurdles toward the ground. Randall and the others reflect on just how much they had in life before the impact of the comet catches up to them, and all of Earth is destroyed.

More than 22,000 years later, the survivors in the pods arrive nude at a different Earth-like planet, which is inhabited by mutant creatures, one of which begins to eat Janie.

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Astronomers Randall Mindy and Kate Dibiasky find evidence that an enormous comet is heading toward Earth within six months time and will wipe out all life on Earth. However, despite their attempts to warn President Janie Orlean and the rest of the public, they treat it as a hoax or a wild conspiracy theory.

Randall and Kate are joined by Dr. Teddy Oglethorpe in their efforts to spread the word of the comet's impact, met with indifference or mockery. Soon, Janie attempts to capitalize on the comet to divert attention from a scandal she is involved in. They initially attempt to send war hero Benedict Drask out into orbit to nuke the comet, but once big tech CEO Peter Isherwell finds out that the comet has enough material in it to mine for profit, the administration changes their tune and plans to allow the comet to hit in order to profit off of it. Randall becomes swept up in the media frenzy, while Kate is shunned for seeming like a conspiracy nut.

Eventually, once the comet starts coming into Earth's atmosphere, the public pays more attention to it, but more for the purposes of money or fame. Despite Randall and Kate's best efforts to combat the comet and save the population, Janie and Peter's teams outnumber them and still attempt to mine the comet, only to be met with failure as well. Randall, Kate, and their loved ones gather to spend their final moments together, while Janie and all the other rich people (except her son Jason) go into cryosleep to survive the comet's impact. Earth and all life on it is eventually destroyed.

More than 22,000 years later, the survivors arrive at a new planet, with several mutant creatures inhabiting it, and Janie is eaten by one of them.