The novel follows five days in the life of Moses E. Herzog, who, at the age of forty-seven, is having a midlife crisis following his second divorce. He has two estranged children, one by each wife, and is in a relationship with a vibrant woman, Ramona, but finds himself running away from commitment.
Herzog spends much of his time mentally writing letters he never sends. These letters are aimed at friends, family members, and famous figures, including recipients who are dead or who Herzog never knew. The one common thread is that Herzog is always expressing disappointment, either his own in the failings of others or their words, or apologizing for the way he has disappointed others.
Herzog's second wife, Madeleine, has recently left him for Valentine Gersbach, whom Herzog considered a close friend. While still married, Madeleine convinced Herzog to move her and their daughter Junie to Chicago and to arrange for Gersbach and his wife, Phoebe, to move as well. The plans were a ruse, and shortly after arriving in Chicago, Madeleine throws Herzog out and attempts to have him committed to an asylum.
The novel opens with Herzog in his house in Ludeyville, a fictional town in the Berkshires in western Massachusetts. He is contemplating returning to New York to see Ramona, but instead flees to Martha's Vineyard to visit some friends. He arrives at their house, but writes an actual note saying that he has to leave.
Herzog then heads to New York, and, after spending a night with Ramona, he heads to the courthouse to discuss with his lawyer the possibility of regaining custody of his daughter, Junie. He subsequently witnesses a series of court hearings, including one where a woman is charged with beating her three-year-old to death by flinging him against a wall. Moses, already distraught after receiving a letter from Junie's babysitter about an incident in which Valentine locked Junie in the car while he and Madeleine argued inside the house, heads to Chicago. He goes to his stepmother's house and picks up an antique pistol with two bullets in it, forming a vague plan to kill Madeleine and Valentine and run off with Junie.
The plan goes awry when Herzog sees Valentine giving Junie a bath and realizes that she is in no danger. The next day, after taking his daughter to the aquarium, Herzog crashes his car and is charged with possession of a loaded weapon. His brother, the rational Will, picks him up to try and help get him back on his feet. Herzog heads to Ludeyville, where his brother meets him and tries to convince him to check himself into an institution, which Herzog has considered but ultimately decides against. To Will's surprise, Ramona joins them for dinner, and Herzog begins making plans to fix up the house, which, like his life, needs repair but is still structurally sound. Herzog closes by saying that he does not need to write any more letters.
In flashbacks throughout the novel, other critical details of Herzog's life come to light, including his first marriage to Daisy, their son, Marco, the life of Herzog's father, and Herzog's sexual molestation by a stranger on a street in Chicago.
