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.
Fisherman Matt Boyd (Richard Dreyfuss) is fishing in Lake Victoria when a small earthquake hits, splitting the lake floor and causing a whirlpool. Boyd falls in, and is ripped apart by a shoal of piranhas that emerge from the chasm.
A group of soldiers led by Maj. Baker (Bradford Dillman) is ordered to investigate a basement level station which they believed was attacked. After Baker contacts his commander, Gen. Slater (Richard Widmark), they begin to investigate who drove a civilian van into the base. It is revealed to be owned by a scientist named Dr. Bradford Crane (Michael Caine), the only survivor of the attack. Slater orders two helicopters to check for a black mass (revealed to be bees), but the two helicopters are swarmed by the bees and crash, killing the pilots inside. Crane insists to Slater that the base was attacked by the same African killer bees that destroyed the helicopters. Helena Anderson (Katharine Ross), one of the base's doctors, supports Crane's story.
In 1901, mail order bride Joanna (Eleanor Parker) arrives from New Orleans at a South American cocoa plantation to meet her new husband, plantation owner Christopher Leiningen (Charlton Heston), whom she has married by proxy.
A group of animal activists, consisting of Dr. Nikki Riley (Debbie Gibson), Gia (Arden Cho) and Ben (Patrick Hancock), break into a house and steal dozens of exotic pythons before setting them free into the Florida Everglades. Their actions inadvertently cause the snakes to grow into alarming sizes and threaten the ecosystem, as they kill over 72 alligators in a matter of days. Due to the threat of the invasive species, Park Ranger Terry O’Hara (Tiffany) issues permits to the local hunters to exterminate the pythons – much to Nikki’s dismay. However, the hunters themselves – including Terry’s fiancé Justin (Carey Van Dyke) – are quickly eliminated by the giant snakes. Vowing to avenge her fiancé’s death, Terry and Angie (Kathryn Joosten) take boxes of anabolic steroids from Angie’s grandson Manny (Chris Neville) and inject them into dead chickens before feeding them to alligators. Among the steroids is an experimental serum that neutralizes muscle growth inhibitors with a side effect of increased aggression. Meanwhile, Nikki and her group set up cameras all over the Everglades to monitor Terry’s activities. They catch and record Terry and Angie feeding the steroid-laced chickens to the alligators.
Le Méga Shark revient mais il va devoir faire face à un crocodile géant : le Crocosaurus. Attaquant beaucoup d'humains, les deux monstres se battent en duel. L'amiral Calvin et l'agent Hutchinson décident alors d'envoyer le lieutenant Terry McKormick et le chasseur Nigel Putman mettre un terme aux attaques des deux monstres.
Off the coast of Alaska, oceanographer Emma MacNeil (Deborah Gibson) is studying the migration patterns of whales aboard an experimental submarine she took without permission from her employer. Meanwhile, a military helicopter drops experimental sonar transmitters into the water, causing a pod of whales to go out of control and start ramming a nearby glacier. In the chaos, the helicopter crashes into the glacier, and the combined damage breaks the glacier open, thawing two hibernating, prehistoric creatures. MacNeil narrowly avoids destruction as, unknown to her, a giant shark and octopus are freed. Some time later, a drilling platform off the coast of Japan is attacked by the octopus, which has tentacles large enough to wrap around the entire structure. After returning to Point Dume, California, MacNeil investigates the corpse of a beached whale covered with many bloody wounds. Her employer Dick Richie (Mark Hengst) believes them to be from a tanker propeller, but MacNeil insists they appear to be from a creature. Later, she extracts what appears to be a shark’s tooth from one of the wounds. Elsewhere, the huge shark leaps tens of thousands of feet into the air from the ocean and attacks a commercial aircraft, forcing it to crash into the water.
The film focuses on the Orinoco River in Venezuela, where a strain of genetically modified piranha have escaped into an isolated tributary of the river. Through human interference of the local environment, the megapiranha manage to escape from their isolated spot and swim downstream, killing all that crosses their path. The megapiranha gradually make their way towards Florida at the height of the tourist season.