The story describes Augie March's growth from childhood to a fairly stable maturity. Augie, with his brother Simon and the mentally abnormal George have no father and are brought up by their mother who is losing her eyesight, and a tyrannical grandmother-like boarder in very humble circumstances in the rough parts of Chicago. Augie drifts from one situation to another in a free-wheeling manner—jobs, women, homes, education and lifestyle.
Augie March's path seems to be partly self made and partly comes around through chance. In lifestyle he ranges from near adoption by a wealthy couple who spoil him, to a struggle for existence stealing books and helping out friends in desperate straits. His most unusual adventure is his flight to Mexico with the wild and irrepressible Thea who tries to catch lizards with an eagle. Thea attempts to convince Augie to join her in this seemingly impossible task.
His jobs include general assistance to the slightly corrupt Einhorn, helping in a dog training parlour, working for his brother at a coal-tip, and working for the Congress of Industrial Organizations until finally he joins the merchant navy in the war.
Augie attracts and gets involved with a string of different women. Firstly a casual acquaintance as a youth, he gets engaged to a wealthy cousin of his brother's wife. However, through a scandal not of his fault, he is discarded. After a casual affair with Sophie, a Greek hotel maid, he is swept off by Thea, whom he had met when living with the rich Renlings and who forecast their relationship even though he loved her sister. After the fiasco in Mexico, where he suffered a terrible accident on a horse, he and Thea began drifting apart; he spending his time playing cards and she hunting for snakes and lizards in the mountains. Their inevitable split came the night he agreed to drive another woman, Stella, to another town to escape her troubled boyfriend. After the break-up, Augie returned to Chicago and picked back up with Sophie until joining the merchant navy and heading to New York. There he met up with Stella again and married her.
All through the book, Augie is encouraged into education, but never quite seems to make it; he reads a great deal for himself and develops a philosophy of life. Something or somebody always tends to crop up, turning his path before Augie seriously considers returning to education.
During the war, his ship is sunk and he suffers a difficult episode in a lifeboat with a man who turns out to be a lunatic. After rescue, he returns to Stella and the book ends with them living a slightly dubious existence in France, he involved in some fairly shady business deals and she attempting to pursue a career in acting.