A meteorite crashes near the town of Arborville, California. An elderly transient (Frank Collison) discovers, within the sphere, a jelly-like substance (the Blob) that attaches itself to his hand. Three high school students, Brian (Kevin Dillon), the rebellious biker whose next false step will take him to major jail, as this day is precisely his 18th birthday, Meg (Shawnee Smith) the high school pretty girl, and Paul (Donovan Leitch) the successful football player, encounter the man and take him to a hospital. After Brian leaves, Paul witnesses the lower half of the transient's body melting (or disolving or being digested) from exposure to the Blob. As he calls for help, the Blob drops on top of him. Meg arrives to see Paul being dissolved by the growing Blob and while trying to free him his arm is torn from his body, Meg is thrown against a wall and knocked unconscious and the Blob oozes out of the hospital and oozes into a nearby manhole into a sewer.
After Brian and Meg have unsatisfactory encounters with the police who refuses to belive the teens that something is going on, they meet at a diner where Meg tells Brian about the Blob. Brian's disbelief is shattered when the diner's handyman is grabbed and pulled head first through the sink drain by the Blob. It pursues them to the diner's walk-in freezer where it retreats because it cannot tolerate extreme cold. After eating the diner's owner and the town's sheriff, the Blob reenters the sewers.
Meg and Brian return to the police station, where the dispatcher tells them Deputy Briggs (Paul McCrane) is near the meteor-landing site. They discover a military operation led by a scientist, Dr. Meddows (Joe Seneca), who orders the town quarantined. Brian escapes a military van and collects his motorbike.
Meg is taken to town where she learns her younger brother Kevin (Michael Kenworthy) is missing. Meg learns he and his friend Eddie (Douglas Emerson) have sneaked into the local theater to see a slasher film thanks to Eddie's usher brother Anthony (Jamison Newlander). The Blob infiltrates the theater and attacks the staff and then the audience... growing with each person it oborbes and digests. Meg just manages to rescue Eddie and Kevin.
Meanwhile, Brian eavesdrops on Meddows speaking to his assistant Jennings (Robert Axelrod) and learns that the Blob is a biological warfare experiment created during the Cold War. Anthony then reports that he witnessed The Blob chasing Meg, Kevin, and Eddie into the sewers. Brian overhears Meadows decide to trap The Blob in the sewers, and that he is willing to let Meg, Kevin, and Eddie die to do so. Brian is discovered listening in and evades military personnel by driving his motorcycle into the sewers.
In the sewers, Meg, Eddie, and Kevin flee from the Blob. Kevin escapes to the surface by scaling a pipe and squeezing through a grate while Eddie is devoured. Meg is saved by Brian, who confronts Meddows in front of the townsfolk and Briggs. After failing to convince everyone Brian is contaminated and must die, Meddows attempts to shoot Brian, but is killed by the Blob as it drags him into the sewer with one of its tentacles. The Blob then bursts from the sewers in a massive and sicking glob of reddish like jellow proceeds to feast upon the population, proving impervious to the military's attempts to stop it (getting shot multiple times while in the sewer and blown up, which only angered it). In the ensuing panic, the town's Reverend Meeker (Del Close) proclaims 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 monster backs off, and she realizes that it cannot stand cold.
The surviving humans retreat to the town hall and hold the Blob at bay with furniture-barricades and fire extinguishers, but it is a losing battle, as a result with the Blob engulfing half of the building and devouring Briggs. Brian goes to the town's garage and gets a snow maker truck that has canisters of liquid nitrogen attached. Just as the Blob is about to devour Meg and her family, Brian drives to town hall and shoots snow at the creature, which is angered and knocks the truck over. As the Blob surges toward Brian, Meg lures it away from him towards the canisterswhich she has rigged with an explosive charge taken from a dying soldier. She tries to get clear, but snags her foot between two pieces of metal, leaving her dangling upside down. Brian regains consciousness and runs over to free her. The Blob is about to overrun them when the charge goes off, blowing up the canisters and covering the Blob with liquid nitrogen. The creature is flash-frozen, shattering into a mass of crystallized pieces. Moss Woodley (Beau Billingslea) has its remains hauled away to the town ice house.
In the final scene, there is a tent-meeting church service in a field, where Meeker, disfigured by his burn injuries, is now crazed, preaching a doomsday sermon sounding like the Blob's attack. Afterwards, when an old woman asks him when the time of reckoning will come, he replies "Soon... Madame... soon. The Lord will give me a sign", and holds up a glass jar containing a fragment of the Blob that he took from the ice house... which is slowly moving.