The story begins with the birth of the protagonist, Benjamin in 1860. Benjamin is born with the physical appearance of a seventy-year-old man, and when his father first visits him mere hours after his birth he is already able to speak. To avoid embarrassment, Benjamin's father forces him to shave his beard and dye his hair in order to look younger. He also forces Benjamin to play with the other neighborhood boys, and buys him toys and orders him throughout the day to play with them. Benjamin obediently plays with them, but only to please his father as Benjamin has more joy in smoking his father's cigars, reading encyclopedias, and talking to his grandfather. He is even sent to kindergarten at the age of five, but is quickly withdrawn from the class after repeated instances of falling asleep during child-oriented activities.

As the story progresses it soon becomes apparent to the Button family that Benjamin is aging backwards which astounds them beyond belief. At the age of eighteen he enrolls in Yale University. However, having run out of hair-dye on the day that he is supposed to register for classes, the officials at Yale send him away believing that he is a fifty-year-old lunatic.

Several years later, while attending a party with his father (who now looks to be the same age as Benjamin), Benjamin meets the young Hildegarde Moncrief, the daughter of a respected Civil War general. Hildegarde tells Benjamin that she would rather be with an older man because they treat women better. He dances with her, and they quickly fall in love and marry. Benjamin soon takes over his father's hardware business, and he proves to be highly adept at the job, while growing fabulously rich.

As Benjamin "grows younger," he begins to feel healthier and happier, as Fitzgerald says, "the blood flowed with new vigour through his veins." However, his wife ceases to attract him as she ages, and he soon decides to fight in the Spanish-American War. He serves with great distinction and receives a medal for a wound he received at the Battle of San Juan Hill. When he returns home his relationship with his wife deteriorates further, and he becomes more detached from her. He often leaves the house and goes to lavish parties and dances, while his wife is more settled in her ways.

In 1910 Benjamin turns over control of his company to his son, Roscoe, and enrolls at Harvard, with the appearance of a 20-year-old. His first year at Harvard is a great success, and he dominates on the football field. However, by the time Benjamin reaches his senior year he is a frail sixteen-year-old too weak to play football and barely able to cope with the academic load.

Benjamin returns home, and he learns that his wife had moved to Italy. And as the years progress he goes from being a moody teenager to being a young boy and is reluctantly cared for by his son, who treats him very disdainfully, demanding that Benjamin call him "uncle" in front of house guests. Eventually, he looks to be the same age as his own grandson, and even attends kindergarten with him. As his body grows younger, Button slowly begins to lose his memory of his earlier life. The toys and games that he spurned as a newborn begin to interest him. As he reaches the end of his life he becomes a baby, and his nurse Nana takes him for walks and teaches him to say words. His memory deteriorates to the point where he can't remember anything except the immediate present, and eventually, all goes dark.