The plotline follows the airmen of the 256th Squadron while in action over Italy, and their repeated attempts to avoid combat missions that appear to lead to certain death. Their attempts are almost always comical; when an officer refers to the string on a map representing the front line and states that they won't be able to fly if it moves beyond the target, the airmen begin watching the string obsessively until Yossarian secretly moves the string and the mission is cancelled. The officer is not amused, and assigns them a particularly dangerous mission. The ultimate escape is to have oneself declared mentally unfit for duty, but the Air Force has made this impossible through the eponymous Catch-22. In spite of their best efforts, most of the airmen are killed over the span of the novel.
The development of the novel can be split into segments. The first (chapters 1–11) broadly follows the story fragmented between characters, but in a single chronological time in 1943. The second (chapters 12–20) flashes back to focus primarily on the "Great Big Siege of Bologna" before once again jumping to the chronological "present" of 1943 in the third part (chapter 21–25). The fourth (chapters 26–28) flashes back to the origins and growth of Milo's syndicate, with the fifth part (chapter 28–32) returning again to the narrative "present" but keeping to the same tone of the previous four. In the sixth and final part (chapter 32 on) remains in the "present" time but takes a much darker turn and spends the remaining chapters focusing on the serious and brutal nature of war and life in general.
Previously the reader had been cushioned from experiencing the full horror of events, but in the final section the events are laid bare. The horror begins with the attack on the undefended Italian mountain village, with the following chapters involving despair (Doc Daneeka and the Chaplain), disappearance in combat (Orr and Clevinger), disappearance caused by the army (Dunbar) or death of most of Yossarian's friends (Nately, McWatt, Mudd, Kid Sampson, Dobbs, Chief White Halfoat and Hungry Joe), culminating in the unspeakable horrors of Chapter 39, in particular the rape and murder of Michaela, who represents pure innocence. In Chapter 41, the full details of the gruesome death of Snowden are finally revealed.
Despite this, the novel ends on an upbeat note with Yossarian learning of Orr's miraculous escape to Sweden and Yossarian's pledge to follow him there.