Alas, Babylon takes place in the late 1950s, at the height of the Cold War between the United States and the Soviet Union. Randy Bragg, who lives in the small town of Fort Repose, Florida, receives a warning from his brother Mark, an Air Force officer, that a nuclear attack is imminent. Mark sends his wife, Helen, and children, Ben Franklin and Peyton, to Randy Fort Repose, believing they are safer there than in their home near an Air Force base in Omaha, Nebraska.
Randy prepares for their arrival by stockpiling food and supplies and warning the Henrys, a black family who live nearby, and his girlfriend, Lib McGovern. The morning after Mark's wife and children arrive, atomic bombs are dropped on all major cities in the U.S. Washington is destroyed, leaving only a low-level cabinet secretary to lead the nation. When Orlando is bombed, Fort Repose's power supply is cut off, leaving it completely isolated from the rest of the nation.
The town falls into chaos; supplies of food and gas are exhausted, the local doctor and Randy's best friend Dan Gunn has his clinic ravaged by drug addicts, people suffer heart attacks, and a few even commit suicide, notably Edgar Quisenberry, president of the Fort Repose bank.
Randy, his family, his neighbors, and the friends he invites to live with him—Dan Gunn, his girlfriend Lib, and her family—manage to create a system of order and survive. They rely heavily on cooperation, sharing food and crops such as oranges, a safe artesian water supply, and all the skills that each person can contribute. Dan Gunn continues to make house calls with their car, requiring his clients to pay him with a gallon of gasoline. They trade for things they need with other people in town.
Though it initially seemed they had escaped radiation fallout, three Fort Repose residents eventually develop radiation poisoning. It turns out that it is from contaminated jewelry that a man named Porky Logan brought from a nearby city. In order to deal with this, Dan and Randy bury the jewelry in a lead-lined coffin with Porky Logan's body; Randy has to threaten other men in the town with a gun so that they would help with the burial.
Randy has been a great leader up to this point for his band of family, friends, and neighbors at home, but when an announcement is made over the radio that allows all former Army Reserve officers (Randy was one of them in the past) to assume responsibility for safety and organization of their towns, Randy is given official authority. Other citizens respect him more and more as he develops into a true leader. His relationship with Lib develops further and further, until finally they get married on Easter Sunday, months after the nuclear attack, because Randy realized that as the acting authority in the town, he has the power to issue marriage licenses.
Another crisis occurs when Dan Gunn is making a house call; on his way home, highwaymen rob him, taking his car and medical bag. Randy is outraged, and makes a plan to hunt down the highwaymen and kill them as both punishment and a preventative measure to ensure that they do not do the same to someone else. They lure the highwaymen to them with a grocery truck and manage to kill two and capture the other, but in the process Randy's neighbor and trusted friend Malachai is killed.
The months roll on and the tow struggles with many food shortages, notably a loss of salt. By reading the diary of his ancestor, the founder of Fort Repose, Randy locates a beach downriver made entirely of salt, with all the crabs one could catch to bring back and eat.
At long last, planes begin to fly over Fort Repose again; a helicopter lands containing members of a decontamination crew, who pronounce Fort Repose completely free of radiation. One of them is Randy's old friend, who confirms to Helen that her husband Mark unfortunately did not survive the bombing. This leaves her free to admit her feelings for Dan Gunn. The decontamination team offers them an airlift out of Fort Repose, but they all agree that they want to stay with the town and the people they have come to love. In the final lines of the book, it is revealed that the U.S. won the war, but at a great cost.