July 20, 1957. In the small Pennsylvania town of Downington, teenager Steve Andrews (Steve McQueen) and his girlfriend Jane Martin (Aneta Corsaut) are out parking and see a falling star. They drive out to try to find where the meteor landed. An old man (Olin Howland) has heard the meteor crash near his house. He finds the meteor and pokes it with a stick. The rock breaks open to reveal a small jelly-like blob inside. This Blob, a living creature, crawls up the stick and attaches itself to his hand. Unable to scrape or shake it loose (and apparently now in pain), the old man runs hysterically onto the road, where he is seen by Steve, who takes him to see the local doctor, Doctor Hallen.
They reach the clinic when Doc Hallen is about to leave. Hallen anesthetizes the man and sends Steve back to the crash site to gather more information. Hallen decides he must amputate the man's arm which is being consumed by the Blob, calling in his nurse. However, the Blob completely consumes the old man. Now an amorphous creature, it eats the nurse and the doctor while increasing in size.
Steve and Jane return to the office and Steve witnesses the doctor's death. They go to the local police and return to the clinic with the kindly Lt. Dave (Earl Rowe) and cynical Sgt. Bert (John Benson). However, there is no sign of the creature or the doctor, and the police dismiss Steve's story. Steve and Jane are sent home with their fathers but sneak out and retrieve Steve's friends and successfully enlist their help warning the town.
In the meantime, the Blob has consumed a mechanic, the janitor in Mr. Andrew's grocery store, and a bar room of late-night drinkers.
Investigating, Steve and Jane are confronted by the Blob in the grocery store and seek refuge in the walk-in refrigerator. The Blob starts to ooze in under the door but then retreats. Steve and Jane escape and set off the town's fire and air-raid alarms. The whole town gathers and demands to know what is going on. As the townspeople and police angrily confront Steve, the Blob enters the Colonial Theater which is showing horror classic Daughter of Horror engulfing and eating the projectionist before oozing into the cinema seating area.
The patrons run screaming out of the theater, alerting the assembled townspeople to the danger. The Blob leaves the theater, but Jane's little brother appears from the crowd to confront the Blob with his cap gun before running into the adjacent diner. Jane and Steve run in after him but become trapped along with the owner and a waitress.
The Blob (now an enormous mass from all the people it consumed) engulfs the diner and begins to ooze in through the windows while the occupants seek refuge in the cellar. The police try to kill the Blob by dropping a power line onto it, but this fails and only sets the diner ablaze. Defending themselves inside, the diner's owner uses a CO2 fire extinguisher attempting to put out the fire, which also causes the approaching Blob to recoil. Steve remembers that the Blob retreated from the refrigerator, too, and tells Lt. Dave that the Blob apparently cannot stand the cold ("CO2, Dave, CO2!"). Jane's father, Mr. Martin (Elbert Smith), takes Steve's friends to the high school to retrieve fire extinguishers which are used to freeze the Blob. Dave requests an Air Force jet to transport the Blob to the North Pole to keep it frozen. A military plane is shown dropping the Blob into an Arctic landscape. The film ends with the "The End".... which morphs into a question mark (?).