When Marian (Marlene Clark), the wife of geologist Chester Hargis (Godfrey Cambridge), unwittingly thaws out one of her husband's scientific samples, a red gelatinous substance oozes from the canister in which the sample was stored and quietly engulfs their pet kitten. Seemingly energized by the sustenance, the blob oozes out into the yard, where Marian is searching for the kitten. As the creature grasps Marian's legs to engulf her, she faints in terror and succumbs, unknown to Chester, who is watching television in the living room. Soon after, family friend Lisa Clark (Gwynn Gilford) enters the house to find Chester sitting in his reclining chair being dissolved by the ever-expanding blob. Horrified, Lisa races to her boyfriend Bobby Hartford (Robert Walker Jr.) for help, but when they return to the Hargis house, no evidence of the tragedy remains.
Meanwhile, bowling alley owner Edward Fazio (Richard Stahl), having spotted Lisa speeding, reports her to the police and follows her to the house to admonish her. When Lisa tries to explain to the police that her friends are missing, they search the house while Mr. Fazio insists that they arrest her for speeding. After finding nothing suspicious, the police release Bobby and Lisa.
Elsewhere, two teenagers are smoking marijuana in a storm drainage culvert, when policeman Ted Sims (Tim Baar) confronts them. Seeing the red, viscous material dripping into the culvert behind Sims's head, the teenagers warn the policeman, but he suspects they are trying to trick him and ignores their pleas. Within seconds, the blob engulfs Sims and the teenagers.
Later that evening, the blob seeps into a hair salon through the sewer system, swallowing the customer's head and hairdresser's arms during a shampoo at the sink.
Meanwhile, Bobby and Lisa return to her house, where dozens of Bobby's friends are waiting to throw him a surprise birthday party. As the festivities ensue, Lisa, upset that Bobby does not believe her story, asks him to take her to his ranch.
In another part of town, a middle-aged Russian man (Tiger Joe Marsh) is taking a bath when the blob slips under the door and swallows his pet dog as the man watches helplessly. Petrified and naked, the man runs into the street, where police pick him up for exposing himself. Back at the police station, reports of missing persons are piling up.
At Bobby's ranch, the blob, having already consumed three hobos, is growing exponentially, and quickly envelopes Bobby's truck when the couple arrives. Knowing what fate awaits them, Lisa screams for help, but they cannot escape. Suddenly during the tumult, the blob recedes for no apparent reason. Bobby and Lisa then race to a gas station to call Sheriff Jones (Richard Webb) and are told that he is at the bowling tournament. Seeing their friend Joe (Gerrit Graham) and his girlfriend Leslie (Carol Lynley), Bobby and Lisa describe the horrific monster. Although Leslie is convinced of their sincerity, Joe mocks them in disbelief and drives off in his dune buggy to investigate their claims.
As Bobby, Lisa and Leslie make their way to the town bowling tournament to find the sheriff, they are confronted by the blob, which has covered the road and is enveloping Joe and his car. A hysterical Leslie rushes to help Joe, but dies with Joe under the oozing mass.
Taking an alternate route, Bobby and Lisa reach the bowling alley, where Bobby uses the loudspeaker to advise everyone to leave the area, but his warning goes unheeded. Angered by the disruption, Fazio orders his bouncer to bring Bobby and Lisa to his office, where they explain the danger. Meanwhile, the blob, having already devoured the bowling alley mechanic, surges down all the lanes toward the terror-stricken people, who run for their lives.
Bobby, Lisa and Fazio barricade themselves in a broadcast booth high above the adjacent ice rink, which is closed for repairs, and watch as dozens of people succumb to the fast-flowing blob. Using the speaker system, Bobby tells the sheriff and his men, who are waiting outside, that the blob is a giant single-celled animal that can ooze through cracks. As the sheriff and his men dress in riot gear to prepare to attack the creature, Bobby tries to electrocute it with a live wire, but does not succeed. Jones and his deputy shoot at the creature, which is unharmed and subsequently eats the deputy.
Having devoured the remaining public in the facility, the blob seeps into the booth through a hole in the floor. Scrambling to get away from the creature, Bobby knocks over a small refrigerator and spills ice onto the blob, which shrinks from the cold. Realizing that the air conditioner in their truck must have been the reason the blob did not eat them earlier, Bobby and Lisa asks Fazio how to cool the rink to freeze the blob. Meanwhile outside, the sheriff, having lost contact with Bobby, assumes that he and the others have been eaten, and orders his men to dowse the building in gasoline so they can burn the blob, unaware that fire will have little effect on the creature. Inside, Bobby heroically climbs the ropes leading to the rink's switch box. Once the rink's cooling system is on, the blob freezes solid instantaneously.
Bobby then runs out of the building just in time to stop the sheriff from setting it ablaze. Minutes later, the sheriff proudly stands on top of the mounds of the frozen blob to give a television interview about the shapeless monster that almost destroyed their town and possibly the world. Just under his feet, a small section of the blob defrosts from the camera light and begins to engulf the sheriff's boot.....