Following a nuclear test in French Polynesia, the fallout irradiates a lizard's nest. Decades later, an enormous sea creature suddenly attacks a Japanese fishing vessel in the South Pacific, leaving only one fisherman alive. Dr. Niko "Nick" Tatopoulos, an NRC biologist, is sent to Tahiti and to Jamaica, where a wrecked village, footprints, and ship are found. Nick collects skin samples that lead him to believe the creature is an enormous mutant created by nuclear testing. It travels to New York City during the rainiest week of the season, leaving a path of destruction in its wake.
On July 20, 1969, astronaut Jim Lovell hosts a party, where guests watch on television as Neil Armstrong takes his first steps on the Moon during Apollo 11. After the party, Lovell, who had orbited the Moon on Apollo 8, tells his wife Marilyn that he intends to walk on the Moon's surface.
On May 10, 1998, teenage amateur astronomer Leo Biederman discovers an unusual object near the stars Mizar and Alcor at a star party in Richmond, Virginia with his school's astronomy club. His teacher alerts astronomer Dr. Marcus Wolf, who realizes that the object is a comet on a collision course with Earth. Wolf dies in a car accident before he can alert the world.
In October 1991, the commercial fishing boat Andrea Gail returns to port in Gloucester, Massachusetts, with a poor catch. Desperate for money, Captain Billy Tyne (Clooney), convinces the Andrea Gail crew to join him for one more late season fishing expedition. The crew heads out past their usual fishing grounds in the Grand Banks, leaving a developing thunderstorm behind them. Initially unsuccessful, they head to the Flemish Cap, where their luck improves. At the height of their fishing the ice machine breaks; the only way to sell their catch before it spoils is to hurry back to shore. After debating whether to sail through the building storm or to wait it out, the crew decides to risk the storm. However, between the Andrea Gail and Gloucester is a confluence of two powerful weather fronts and a hurricane, which the Andrea Gail crew underestimates.
In 2005, scientists discover an extrasolar planet, which they name Planet G, with conditions similar to Earth. In 2006 NASA transmits a powerful signal from a communications array in Hawaii. Meanwhile, slacker Alex Hopper gets arrested while attempting to impress Sam Shane, daughter of U.S. Pacific Fleet commander Admiral Terrance Shane. Stone Hopper, Alex's older brother and a naval officer, is infuriated at Alex's lack of motivation and forces Alex to also sign up and earn a commission in the U.S. Navy.
A year after the events of Extinction, the Alice clones (Milla Jovovich) attempt to kill Albert Wesker (Shawn Roberts) at the current Umbrella Headquarters, Tokyo. The clones manage to kill the entire branch, but Wesker makes his way to his private charter tiltrotor plane and escapes before activating a bomb, leaving a massive sinkhole. However, the real Alice boarded his aircraft beforehand. As she pulls a gun on him, Wesker injects her with Anti-Virus before the lack of a pilot makes the aircraft crash in the mountains outside Tokyo. Only Alice emerges from the crash alive.
Alice (Milla Jovovich) and the others on the Umbrella Corporation freighter Arcadia face an attack by a fleet of tiltrotors led by Alice's former ally, Jill Valentine (Sienna Guillory), who is being mind controlled by Umbrella through a scarab device attached to her chest. Alice causes a tiltrotor to crash into Arcadia, resulting in an explosion that knocks her out and into the water. The fates of Chris Redfield, Claire Redfield and K-Mart are ambiguous.
In 1928, a solitary mountaineer encounters a glowing sphere. He loses consciousness and when he wakes, the sphere has gone and there is a scar on his hand where a sample of his DNA has been taken.
In 1979 a priest at the Vatican sees a comet arching over the moon (described as the "Eye of God"), heralding the birth of one chosen to be the mother of Satan's child. The priest is sent on a mission by the pope (Mark Margolis) to find and protect the girl from Satan, although a few Vatican knights (led by a corrupt cardinal (Michael O'Hagan)) insist that she must die. In New York a newborn girl, Christine York (Robin Tunney), is identified by Satanists (including her physician, Dr. Abel (Udo Kier), and her nurse and future guardian, Mabel (Miriam Margolyes)) as the person chosen to bear Satan's child on New Year's Eve, 1999. The Satanists perform occult rites on the newborn.
Henry Bennett (Ewan McGregor), his physician wife Maria (Naomi Watts), and their three sons Lucas (Tom Holland), Tomas (Samuel Joslin), and Simon (Oaklee Pendergrast) go on a Christmas holiday in 2004 to Khao Lak, Thailand. Arriving on Christmas Eve, they settle in and begin to enjoy the brand new Orchid Beach Resort. Two days later the massive 2004 tsunami inundates the area.
Motaba, a fictional virus which causes a deadly fever, is discovered in the African jungle in 1967. To keep the virus a secret, U.S. Army officers Donald McClintock (Donald Sutherland) and William Ford (Morgan Freeman) destroy the camp where it was found.
On the MS Poseidon, a luxury ocean liner, former New York City Mayor and fireman, Robert Ramsey (Kurt Russell), is traveling with his daughter Jennifer (Emmy Rossum) and her boyfriend Christian (Mike Vogel), soon to be engaged. Also on board is professional gambler Dylan Johns (Josh Lucas), architect Richard Nelson (Richard Dreyfuss), Maggie James (Jacinda Barrett) and her son, Conor (Jimmy Bennett), stowaway Elena (Mía Maestro), and waiter Valentin (Freddy Rodriguez).
Dr. Harry Dalton (Pierce Brosnan), a volcanologist of the United States Geological Survey, and his partner Marianne (Walker Brandt), are studying volcanic activity in Colombia when the volcano erupts. Marianne is killed by a piece of falling debris, leaving Harry remorseful about her death, believing it could have been prevented by evacuating sooner.
The film is presented as found footage from a personal video camera recovered by the United States Department of Defense. A disclaimer text states that the footage is of a case designated "Cloverfield" and was found in area US447 "formerly known as Central Park". The video consists primarily of segments taped the night of Friday, May 22, 2009. Occasionally, older segments are shown from a previous video that was mostly taped over.