In New York City's Central Park, people begin committing mass suicide. Initially believed to be caused by a bio-terrorist attack using an airborne neurotoxin, the behavior quickly spreads across the northeastern United States. Elliot Moore, a high school science teacher in Philadelphia, hears about the attacks and decides to go to Harrisburg by train with his wife, Alma. They are accompanied by his friend Julian and Julian's eight-year-old daughter Jess. Julian's wife is stuck in Philadelphia but is expected to meet them in Harrisburg. The train loses all radio contact en route and stops at a small town. They receive word that Philadelphia has been attacked by the toxin and Julian's wife was not able to get on the train to Harrisburg. Julian decides to go look for her, leaving his daughter with the Moores while he hitches a ride. However, the town has already been hit by the toxin. Succumbing to it, the driver and Julian both commit suicide.
On September 11, 2001, Port Authority Police officers John McLoughlin and Will Jimeno are patrolling the Port Authority Bus Terminal in Midtown Manhattan when they see a plane fly dangerously low overhead. As all of the police officers return to the station, they see on TV that the North Tower of the World Trade Center has been hit by the plane. Sergeant McLoughlin assigns many of the officers to assist in a precautionary evacuation attempt of the North Tower and they board a Metropolitan Transit Authority bus. On the bus, they hear reports that the South Tower is also hit by another plane. When they arrive at the World Trade Center, they realize the extent of the disaster, and see one of the victims jump out of the towers to certain death. The men proceed to get safety equipment from Building 5 and enter the concourse between the towers.
A group of high school students are in a car together in the night as a storm is brewing. When the storm gets worse, they look up ahead and see a tornado approaching. A girl begs for them to go, but the boy recording on a camera gets out to video tape the tornado. He gets back in the car, but the tornado picks them up before they can escape, killing them all.
In Upstate New York, a waste management firm loads barrels of toxic waste onto trucks, intending to illegally dispose of them. They are shown heading into a tunnel under the Hudson River between Lower Manhattan and Jersey City, New Jersey along with several other commuters, including struggling playwright Maddy Thompson (Amy Brenneman), some young offenders, a vacationing family, an elderly couple, and a mountain climber named Roy Nord (Viggo Mortensen). Meanwhile, a gang of diamond thieves in a stolen car try to escape the NYPD by racing into the tunnel. The gang force their way through the north tube traffic, spilling the diamonds all over the floor of the car. While a female thief tries to retrieve them, she pushes the gas pedal to the floor, causing the driver to lose control, smashing though a security booth and into one of the trucks, killing them instantly. The waste barrels explode, causing the other trucks to explode and setting off a chain reaction. The tunnel entrances cave in, and a devastating fireball sweeps through the tunnel, incinerating thousands of cars and people.
In 1959, student Lucinda Embry (Lara Robinson) hears whispers as she stares at the sun. When her class is chosen to contribute to the school's time capsule, each child is asked to draw what they believe the future will look like. Lucinda writes a page of seemingly random numbers and adds it to her elementary school's time capsule, which is set to be opened in 50 years. Lucinda's teacher calls for the pupils to finish but Lucinda continues before her teacher takes it off her desk unfinished. Lucinda then goes missing after the time capsule is dedicated, and is found by her teacher, Mrs. Taylor (Danielle Carter), in a utility closet scratching numbers into the door with her fingernails bleeding.
Alice (Milla Jovovich) wakes up disoriented in a mansion. She wanders through the halls, where she defeats several obstacles, including a laser beam obstacle (from the first film) and a giant blade that falls from the ceiling. However, she is eventually killed by a miniature machine gun. Her body is dumped into a pit filled with hundreds of Alice clones. The camera zooms out to show a shack camouflaging the facility's above-ground entrance - with the rest of the facility located underground, surrounded by a high fence and thousands of zombies.
Returning from a Hong Kong business trip, Beth Emhoff has a layover in Chicago to have sex with a former lover before returning to her family in suburban Minneapolis. She appears to have contracted a cold during her trip. Her six-year-old son from a previous marriage, Clark, also becomes symptomatic and is sent home from school. Beth's condition worsens and two days later she collapses with severe seizures. Her husband, Mitch, rushes her to the hospital, but she dies of an unknown cause.
In the year 2058, Earth will soon be uninhabitable due to irreversible effects of pollution. The United Global Space Force prepares the first launch for the colonization of a distant planet much like our own. Meanwhile, a terrorist group, the Global Sedition, wants to interrupt the colonization to be able to take over the same planet themselves. Professor John Robinson, lead scientist of the Jupiter Mission, prepares to take his wife Maureen, daughters Judy and Penny and son Will on a 10-year mission in suspended animation to the nearby planet Alpha Prime, where they will build a companion "hypergate" to the one orbiting Earth. The project is accelerated after Global Sedition terrorists attack Earth's hypergate, but are stopped by fighter pilots, one of whom is Major Don West. When the pilot for the Jupiter Mission is murdered, West is assigned as his replacement.
30 days after the contamination of The Hive seen in Resident Evil (2002), the Umbrella Corporation unwisely sends in a research team to re-open the complex and investigate the incident, since no one survived except Alice and Matt Addison, and as Alice was experimented on, Matt was put into a mysterious "Nemesis Program". When the team reprograms and opens the sealed blast doors, they are slaughtered by the massive crowd of infected.
German U-boat U-571 is immobilized by a British destroyer. The US Navy submarine S-33 has been modified to resemble a German U-boat to steal the Enigma coding device and sink the U-571.
Jay Baruchel arrives in Los Angeles to visit with old friend and fellow actor Seth Rogen, who invites him to attend a housewarming party hosted by James Franco. Jay is uncomfortable being around so many people he hardly knows, so Seth accompanies him to a convenience store for cigarettes.
An earthquake strikes the city of Los Angeles. Mike Roark (Tommy Lee Jones), the head of the city's Office of Emergency Management, insists on coming to work to help out with the crisis, even though he has taken a vacation with his daughter Kelly (Gaby Hoffmann). His associate Emmit Reese (Don Cheadle) notes the quake caused no major damage, but seven utility workers are later burned to death in a storm drain, one escaped and survived but was severely burned on one side of his face at MacArthur Park. As a precaution, Roark tries to halt the subway lines which run parallel to where the deaths took place, but Los Angeles MTA Chairman Stan Olber (John Carroll Lynch) declines, feeling there is no threat to the trains. Against regulations, Roark and a colleague Gator Harris (Michael Rispoli) venture down the storm sewer in the park to investigate. They are nearly burned to death when hot gases suddenly spew out of a crack in the concrete lining and flood the tunnel. Geologist Dr. Amy Barnes (Anne Heche) believes a volcano may be rapidly forming beneath the city with magma flowing underground (similar to the formation of the Mexican volcano Parícutin which emerged and grew tremendously in just one week) but cannot come up with enough evidence for Roark to take action.
In the 23rd century, Earth has become a space-faring federation. While colonizing new planets, humans have encountered an insectoid species known as Arachnids or "Bugs", with their home being the distant world Klendathu. The bugs appear to be little more than killing machines, though there are suggestions that they were provoked by the intrusion of humans into their habitats.
In 1918, the young Jiro Horikoshi longs to become a pilot, but his nearsightedness prevents it. He reads about the famous Italian aircraft designer Giovanni Battista Caproni, and dreams about him that night. In the dream, Caproni tells him that building planes is better than flying them.
Architect Doug Roberts (Newman) returns to San Francisco for the dedication of the Glass Tower, which he designed for owner James Duncan (Holden). At 138 stories (1,800 ft/550 m), it is the world's tallest building. Shortly after his arrival, an electrical short starts an undetected fire on the 81st floor while Roberts accuses the building's electrical engineer, Roger Simmons (Chamberlain), of cutting corners. Simmons insists the building is up to standards.