A small meteorite falls to earth near the town of Arborville, Colorado. An elderly transient discovers, within the hollow sphere, a bizarre, jelly-like substance (the Blob) which attaches itself to his hand. Three high-schoolers, punk Brian Flagg (Dillon), cheerleader Meg Penny (Smith) and her footballer-date Paul (Leitch) encounter the fleeing man and take him to a local hospital. After Brian leaves, Paul witnesses the transient and a doctor being melted down from physical encounters with this substance. As he calls for help (in an office), he looks up only to see the blob suddenly drop down, right on top of him. Meg comes running in to see Paul completely covered, all of him being consumed by the now ever-growing Blob which (after discarding a limb) then oozes out of the hospital and enters the town sewer system.

After both Brian and Meg have unsatisfactory encounters with the police, they meet in the town diner where she tells him about the Blob. His disbelief is shattered when they see the diner's handyman sucked (face first) down a sink-drain by the Blob. It chases them into the diner's walk-in freezer where, for some reason, it retreats. After eating the diner's owner (by trapping then crushing her in a phone box) and the town's sheriff, the organism reenters the sewers.

Meg and Brian go to the police station, where the dispatcher tells them deputy Briggs (McCrane) is near the meteor-landing site. They go and discover a military operation led by a scientist, Dr. Meddows (Seneca), who orders the town placed under quarantine. Brian escapes from a military van and goes to collect his motorbike.

Meg is taken back to town where she learns her little brother Kevin (Kenworthy) is missing. Meg finds him and his friend Eddie (Emerson) having snuck into the local theatre to see a slasher movie thanks to Ed's usher brother Antony (Newlander). She rescues the two from amidst a blob rampage as it consumes both staff and visitors alike.

After picking up his bike, Brian eavesdrops on the ecstatic Meddows to his p.a Jennings (Axelrod) and learns that the creature is a biological warfare experiment gone wrong. He also learns from Antony, that Meg Kevin and Eddie are in the sewers and Meddows is secretly willing to let them die to contain the creature. Brian is discovered listening in and evades military personel by driving his motorcycle into the sewer system.

Down below, Meg, Kevin, and a hysterical Eddie are still fleeing from the monster as it devours sewer rats whilst pursing them through the waist deep water. Kevin escapes to the surface by scaling a pipe and squeezng through a grate while Eddie is seized, pulled back and under. Meg dives back into the water to pull him free, only to find him partially covered by the blob as it tears him from her grasp, to be devoured. Meg is subsequently saved by Brian, who confronts Meddows (who'd tried to entrap them below ground) in front of the townsfolk and Briggs. The scientist (failing to convince everyone, he's contaminated and must die) attempts to shoot Brian, but the Blob snatches Meddows (who fires wildly into the air) and drags him back down a manhole to his death (flooding his suit in the process). The remaining soldiers now led by Col. Hargis (Rader) throw an explosive charge down into the sewer; but this does nothing more than anger the creature, which bursts onto the surface, landing on top of Rader (who fails to further blow it up) before proceeding to squash and feast upon the assembled population. In the ensuring panic, the town's Reverend Meeker (Close) is proclaiming the scene to be the prophesied end of the world, when a failed flamethrower attack on the Blob sets him ablaze. Meg saves him with a fire extinguisher, and in the process blasts the Blob with it. The thing backs off, and she realizes why it couldn't come into the freezer: it can't stand cold.

The surviving humans retreat to town hall and hold the Blob at bay with furniture-barricades and fire extinguishers, but it is a losing battle; Briggs is among the casualties as the blob bursts in, folding him in half as it drags him outside. Brian goes to the town's garage and gets a snow maker truck that has two canisters of liquid nitrogen attached to it. He drives to town hall and shoots snow at the creature, but it knocks the truck over. After helping Brian get clear, Meg takes an explosive charge from a dead soldier and blows up the canisters, covering the Blob with the liquid nitrogen. Brian, Meg and then Kevin look on as the creature seems to wail as it is flash-frozen shattering into a exploding mass of crystallized pieces which are scattered across the streets, admist a mushroom cloud of howling winds. Moss Woodley (Billingslea) has it's frozen remains hauled away by dump truck to the town icehouse as Meg embraces both her brother and Brian each one covered in frost.

The film cuts to a tent-meeting in a field, where Meeker, disfigured by his burn injures, (notably surrounding his right eye) and is now crazed, preaching a doomsday sermon to an enthralled congregation. Asked when the time of reckoning will come, he replies "Soon...Maam...soon...when the lord gives me a sign!" and holds up a glass jar containing a fragment of the Blob, that is steadily moving.

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