The book follows the lives of a group of men in a bombing squadron based on the island of Pianosa during World War II. The beginning is set in the base hospital where Yossarian is dealing with a supposed liver ailment. There he becomes bored while censoring letters and starts to sign his name on the letters as "Washington Irving." This causes a C.I.D. man to be placed undercover in the hospital to find out who is "Washington Irving."

We also meet Yossarian's tent mate Orr and his friends Hungry Joe, Doc, Havermeyer, and Clevinger. Among the men in the squadron is Lieutenant Milo Minderbinder, who knows how to get anything for anyone, if the price is right.

Major Major Major is put in charge of the squadron when Major Duluth is killed. Major Major does not like being in charge of the unit because it is dull. Out of boredom he also begins to sign the papers that come across his desk with the name Washington Irving. This brings a second C.I.D. man to find out who this Washington Irving is. The Major finally solves all his problems by making himself permanently unavailable to everyone.

Colonel Cathcart, the group commander, has volunteered the men to bomb ammunition dumps in Bologna. This makes the men afraid, because Bologna is known to be dangerous to fly over. Yossarian is afraid of the Bologna mission, so he instigates several delaying tactics, such as having the cook make the men sick by adding detergent to the food. Yossarian wants to be declared crazy because then he will be grounded. It is during this time Doc Daneeka explains what a Catch-22 is: if a man can tell the doctors he is crazy, then he is considered sane and therefore can fly. If he goes crazy and does not tell anyone, then he is still allowed to fly. In essence it is a no win situation. Yossarian sabotages his intercom system in order to force his plane to turn back. He is reprimanded and forced to fly on the lead bombardier the next day. During this run, the planes run into heavy flak and Orr's damaged plane has to crash land.

Yossarian and some of his friends go to Rome for some rest, here Nately finds his prostitute girlfriend. After their return from Rome the men are informed that the number of missions needed to go home has been raised from thirty-five to forty. Colonel Cathcart is always looking for a way to stand out, such as having his men fly the most missions. He sees an article in a magazine about a squadron in which the chaplain said a prayer before every mission. He wants his chaplain to do the same, but without mentioning God. The chaplain tells him God is always in his prayers, so Cathcart dropped the idea. Colonel Cathcart is also trying to impress General Dreedle, but he never succeeds. Corporal Whitcomb, the chaplain's aid, has told the C.I.D. man that the chaplain is the man signing Washington Irving's name to papers. Corporal Whitcomb wants the chaplain's job.

Yossarian loses his nerve during a mission in which the co-pilot wrenches the controls away from the pilot. During this dive, the gunner, Snowden, is wounded and dies from his wounds, while on another mission, Yossarian has his leg injured, therefore he doesn't want to fly anymore.

Also, while all this is going on, Milo, the mess officer, forms a syndicate providing everything from food to bombing raids for both the Allies and the Germans. Yossarian tells a lie about having dreams about fish, to the psychiatrist, who deems him unfit to be in the military. Unfortunately, the psychiatrist mixes Yossarian up with another soldier and sends the wrong man home. During this time, Orr is sent on the mission from which he never returns.

McWatt on a training run with some new soldiers, flies too close to Kid Sampson, who is on a raft in the water. He cuts Sampson in half, killing him. McWatt has everyone parachute out and then crashes the plane into a mountain.

All the soldiers are reeling from the loss of McWatt and Sampson, but Nately wants to fly more missions. He needs to stay close to his girlfriend in Rome. So Yossarian enlists Milo's help in talking Cathcart into allowing Nately to continue flying; Milo is successful. Unfortunately on the next mission, his plane collides with another plane killing Nately. Yossarian tells Nately's girlfriend of his death and she reacts by trying to kill him. She even goes so far as to come to the base to try to kill him. Yossarian finds out later that she and her kid sister have been kicked out of their apartment by the MPs.

Yossarian goes AWOL, with the help of Milo, to find Nately's girlfriend and her sister. Milo is not much help and Yossarian is finally arrested by the MPs for going AWOL. He is brought back to Colonel Cathcart's office where he is given the opportunity to return to the States if he acts like he is friends with the colonel. He accepts, but Nately's girlfriend, dressed as a private stabs him on his way out of the office. While in the hospital recovering he decides to changes his mind, he would rather run away. It is then the chaplain tells him the news that Orr is alive and in Sweden. Yossarian at last is given hope. He decides to run away to Rome to find Nately's girlfriend's sister and take her to Sweden with him.

This book is about how the army can be one of the most illogical organizations ever created; how the common good is often overlooked for the individual needs, but that hope can be seen in the courageous actions of others. That just because it seems like humanity is falling apart around you, it does not mean a person has to lose their humanity.