The novel is set during the Second World War on a fictional island in the Mediterranean between Italy and Corsica. Captain John Yossarian is a man who does not want to participate in the war but is unfortunately stationed in this war zone. Un swayed by national ideals or abstract principles, Yossarian is furious that his life is in constant danger through no fault of his own. He has a strong desire to live and is determined to be immortal or die trying. As a result, he spends a great deal of his time in the hospital, faking various illnesses in order to avoid the war.

As the novel progresses through its loosely connected series of recurring stories and anecdotes, Yossarian is continually troubled by his memory of Snowden, a soldier who died in his arms on a mission when Yossarian lost all desire to participate in the war. Yossarian is placed in ridiculous, absurd, desperate, and tragic circumstances—he sees friends die and disappear, his squadron gets bombed by its own mess officer, and colonels and generals volunteer their men for the most perilous battle in order to enhance their own reputations.

Catch-22 is a law defined in various ways throughout the novel. First, Yossarian discovers that it is possible to be discharged from military service because of insanity. Always looking for a way out, Yossarian claims that he is insane, only to find out that by claiming that he is insane he has proved that he is obviously sane.

His friend Nately falls in love with a whore from Rome and woos her constantly, despite her continued indifference and the fact that her kid sister constantly interferes with their romantic rendezvous. Finally, she falls in love with Nately, but he is killed on his very next mission. When Yossarian brings her the bad news, she blames him for Nately’s death and tries to stab him every time she sees him thereafter. Another subplot follows the rise of the black-market empire of Milo Minderbinder, the squadron’s mess hall officer. Milo runs a syndicate in which he borrows military planes and pilots to transport food between various points in Europe, making a massive profit from his sales.

Although he claims that "everyone has a share” in the syndicate, this promise is later proven false. Milo’s enterprise flourishes nonetheless, and he is revered almost religiously by communities all over Europe.

Yossarian, troubled by Nately’s death, refuses to fly any more missions. He wanders the streets of Rome, encountering every kind of human horror—rape, disease, murder. He is eventually arrested for being in Rome without a pass, and his superior officers, Colonel Cathcart and Colonel Korn, offer him a choice. He can either face a court-martial or be released and sent home with an honorable discharge.

There is only one condition: in order to be released, he must approve of Cathcart and Korn and state his support for their policy, which requires all the men in the squadron to fly eighty missions. Although he is tempted by the offer, Yossarian realizes that to comply would be to endanger the lives of other innocent men. He decides instead to desert the army and flee to neutral Sweden. In doing so, he turns his back on the dehumanizing machinery of the military, rejects the rule of Catch-22, and strives to gain control of his own life.

Catch-22 is book that brings out everything about war and human character in a fantastically cynical manner.

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