Catch-22 is a difficult book to summarize due to the way it jumps between various points in time. Also, much of what happens are small vignettes about the characters, and do not strictly move the overarching narrative forward.

Yossarian is a captain in a squadron of bombardier stationed in Pianosa, an island off the coast of Italy. He chose to join the air force because he wanted the pilot's training to last long enough so that the war would be over before he was shipped overseas. The squadron he is in continually gets the number of missions they must run increased each time men begin to reach the next milestone. At first it is in the 30s, but by the end of the book it is up to 80.

Yossarian's roommate Orr crashes his plane on every mission he goes out on. Orr is also very handy, and adds many additions to make their tent better. There is a "dead man" in Yossarian's tent who they can't get rid of (a soldier who died before officially joining the squadron). Yossarian spends as much time in the hospital between missions to avoid flying more missions.

On one of Yossarian's missions, another man on the plane (Snowden) is hit by flac. Yossarian attempts to help him, bandaging his leg, but he discovers that there is another would in his stomach that has killed him. On another mission, Yossarian doesn't drop his bombs on the first pass over a bridge, so turns around to try again. This time he succeeds in destroying the bridge, but another plane in the formation is shot down and a man is killed. Yossarian is promoted and receives a medal to cover up his mistake of not dropping the bombs the first time.

Orr crashes his plane, and gets separated from the others in his plane on the ocean and disappears. Hungry Joe has nightmares whenever he isn't flying missions and is waiting to go home. Havermeyer always flies straight for the target and doesn't take evasive action. Yossarian always takes as much evasive action as he can.

McWatt is trying to scare a few new recruits, so he flies low over the beach, and Kid Sampson jumps up to touch the plane. Kid Sampson is cut in half. McWatt makes the others in his plane jump off with their parachutes and then crashes himself into a mountain.

Nately wants to stay even after flying 70 missions so he doesn't lose track of the prostitute he's fallen in love with. He is killed on the next mission and the prostitute tries to kill Yossarian repeatedly after he brings her the news. Clevinger, who always gets heated over moral debates, disappears into a cloud.

Yossarian refuses to fly anymore missions and morale around the squadron begins to degrade. Colonel Catchart and Colonel Korn offer him a deal that, if he says nice things about them, they will send him home a major. He agrees. Yossarian is stabbed by Nately's girlfriend, and put into the hospital. He recovers and decides not to take the deal. The chaplain runs in to tell Yossarian that Orr reached Sweden, and Yossarian realizes that all of Orr's crashes were just practice for this, remembering Orr even asked Yossarian to join him. Yossarian decides to run to Sweden to join Orr.