Paranoid Brigadier General Jack D. Ripper of Burpelson Air Force Base, convinced that the Soviets are contaminating the "precious bodily fluids" of Americans, launches a nuclear attack on the USSR without the knowledge of his superiors, including President Merkin Muffley. Ripper issues Plan R to the patrolling B-52 bombers, ordering them to attack Soviet targets, which is only supposed to be implemented if the entire chain of command is disrupted by an enemy attack. With the bombers approaching their targets and the Soviet Union preparing a counter-strike, the tension escalates at the Pentagon’s War Room, where President Muffley, his advisors, and the Pentagon brass, including bombastic General Buck Turgidson, scramble to recall the bombers.

In the War Room, President Muffley desperately consults with his advisors, including the eccentric ex-Nazi scientist Dr. Strangelove, on how to avert a global catastrophe. Meanwhile, at Burpelson, Group Captain Lionel Mandrake of the UK Royal Air Force, Ripper's executive officer, uncovers the mad General's plan and tries to stop it. Communication failure and Ripper's extreme security measures complicate attempts to recall the B-52s. As the world stands on the brink of nuclear Armageddon, the characters expose their personal and political absurdities, shedding a darkly comedic light on the Cold War fears and the concept of Mutually Assured Destruction (MAD).