A nuclear submarine on maneuvers in the Pacific Ocean, captained by Commander Pete Mathews (Kenneth Tobey), comes into contact with a massive sonar return. The commander attempts to outrun and outmaneuver the sonar object, but cannot. The boat is disabled but manages to free itself and return to Pearl Harbor. Tissue from a huge sea creature is discovered jammed in the submarine's dive planes.
A co-ed team of marine biologists, Professor Lesley Joyce (Faith Domergue) and John Carter (Donald Curtis) of Harvard University, is called in; they identify the tissue as being a small part of a gigantic octopus. The military authorities scoff, but are finally persuaded after receiving reports of missing swimmers and ships at sea being pulled under by a large animal. Both scientists conclude that the creature is from the Mindanao Deep, having been forced from its natural habitat by hydrogen bomb testing in the area, which has made the giant octopus radioactive, driving off its natural food supply.
The scientists suggest the disappearances of a Japanese fishing fleet and a Siberian seal boat may be the work of the foraging giant. Both Pete and the Navy representatives express doubt and demand further proof. Later, as Pete assists John and Lesley, a report comes in of an attack on a Canadian freighter; several men escaped in a raft. The survivors are questioned by psychiatrists, and when the first sailor's description of a creature with giant tentacles is met with skepticism, the other sailors refuse to testify. Lesley is able to convince the first sailor to repeat his story for government officials, who then have the evidence they need. The U.S. government halts all sea traffic in the North Pacific without revealing the reason. John flies out to sea to trace a missing ship, while Pete and Lesley follow up on a report of five missing people off the coast of Oregon.
The local sheriff, Bill Nash (Harry Lauter), takes Pete and Lesley to the site of the attack, where they find a giant suction cup imprint in the beach sand. (At this point, the two have become physically intimate.) They then request that John join them. Bill is later attacked along the beach by the giant octopus, right in front of the two scientists. They escape, and together they hastily arrange for all Pacific coast waters to be mined before departing for San Francisco and the Navy's headquarters.
An electrified safety net is strung underwater across the entrance to San Francisco Bay to protect the Golden Gate Bridge, which has also been electrified. John takes a helicopter along the shoreline and baits the sea with dead sharks in an effort to lure the creature inland. Lesley demonstrates to reporters a special jet-propelled atomic torpedo, which they hope to fire at the giant octopus, while driving it back to the open sea before detonating the weapon. Later that day, the creature demolishes the underwater net, irritated by the electrical voltage, and heads toward San Francisco.
The navy orders the Golden Gate Bridge abandoned, but when John learns that the electric circuit there has been left on, he races to the bridge to shut it off. The creature, however, catches sight of the bridge and attacks it, the electrical voltage irritating it even more. Pete is able to rescue John just before a bridge section is brought down by a giant tentacle.
The residents of San Francisco panic and begin a mass exodus down the peninsula. The navy struggles to evacuate the Embarcadero and the Ferry Building, which is battered by the creature's giant tentacles. When more people are attacked and killed, the Defense Department authorizes Pete to take out the submarine and fire the torpedo; John joins Pete while Lesley remains at the base.
Flamethrowers push the giant tentacles back into the sea, but when Pete fires the jet torpedo into the creature, it grabs the submarine. Using an aqualung, Pete swims up to the massive body and places explosive charges before being knocked out by the shockwaves from the premature explosion. John then swims out and shoots at one of its eyes, forcing the giant octopus to release the submarine; he then pulls Pete to safety. Back at the base, as the creature turns toward the open sea, the torpedo is detonated, completely destroying the giant cephalopod. The trio celebrate at a restaurant, where Pete makes an impromptu proposal, and Lesley accepts.
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