United States Air Force Brigadier General Jack D. Ripper is commander of Burpelson Air Force Base, which houses the SAC 843rd Bomb Wing equipped with B-52 bombers. The 843rd is currently on airborne alert, in flight just hours from the Soviet border.

General Ripper explains to Group Captain Mandrake how he first discovered the Communist plot to pollute Americans' "precious bodily fluids."
Ripper orders his executive officer, Group Captain Lionel Mandrake of the UK Royal Air Force, to put the base on alert, asserting that it is not a drill, and orders him to issue Wing Attack Plan R to the patrolling aircraft, including one commanded by Major T. J. "King" Kong. All of the aircraft commence an attack flight on Russia, and allow communications only through the CRM 114 discriminator.

Mandrake discovers that no order for war has been received, and tries to stop Ripper, who locks them both in his office. Ripper tells Mandrake that he believes the Soviets have been using fluoridation of United States' water supplies to pollute the "precious bodily fluids" of Americans.

At the Pentagon, General Buck Turgidson briefs President Merkin Muffley and several other top officers and aides about the attack in the "War Room". Muffley is shocked to learn that such orders could be given without his authorization, but Turgidson reminds him that Plan R – enabling a senior officer to launch a strike against the Soviets if all superiors up to the President have been killed in a first strike on Washington D.C. – allows such an action. Turgidson reports that his men are cycling through every CRM code to issue the stand-down order but this could take over two days. Muffley orders Turgidson to storm the base and seize Ripper, though Turgidson warns that Ripper may have already alerted his men to this possibility.

Turgidson attempts to convince Muffley to let the attack continue, as their first strike on the Soviets would wipe out the majority of the Soviet missiles, and the few remaining would only cost a few million American lives. Muffley refuses, and instead brings Soviet ambassador Alexei de Sadeski (Peter Bull) into the War Room, despite Turgidson's protest, to get Soviet premier Dimitri Kisov on the "Hot Line." The President tells the Premier, who is drunk, about the situation, and suggests that the USSR fire upon the planes to stop the attack.

After a heated discussion, the ambassador explains that the Soviet Union has created a doomsday device consisting of 50 buried bombs with "Cobalt Thorium G" set to detonate should any nuclear attack strike their country. The Soviets had conceived of this system after reading a New York Times article claiming the United States was working on such a device. The President's wheelchair-bound scientific advisor, former Nazi Dr. Strangelove, is skeptical, noting that a doomsday device would only be an effective deterrent if everyone knew about it. Sadeski admits they had plans to reveal its existence the following week at a Soviet party conference in honor of the Premier, "who loves surprises."

Aircraft commander Major T. J. "King" Kong riding the bomb.
United States Army forces arrive at Burpelson, but, as predicted, the base's troops take the troops to be Soviets in disguise and open fire. The Army forces eventually take over the base and Ripper shoots himself, fearing he will be tortured into revealing the recall code. Colonel "Bat" Guano forces his way into Ripper's office. He suspects Mandrake of being the enemy