All the King's Men is the story of the rise and fall of a political titan in the Deep South during the 1930s. Willie Stark rises from hardscrabble poverty to become governor of his state and its most powerful political figure; he blackmails and bullies his enemies into submission, and institutes a radical series of liberal reforms designed to tax the rich and ease the burden of the state's poor farmers. He is beset with enemies—most notably Sam MacMurfee, a defeated former governor who constantly searches for ways to undermine Willie's power—and surrounded by a rough mix of political allies and hired thugs, from the bodyguard Sugar-Boy O'Sheean to the fat, obsequious Tiny Duffy.

All the King's Men is also the story of Jack Burden, the scion of one of the state's aristocratic dynasties, who turns his back on his genteel upbringing and becomes Willie Stark's right-hand man. Jack uses his considerable talents as a historical researcher to dig up the unpleasant secrets of Willie's enemies, which are then used for purposes of blackmail. Cynical and lacking in ambition, Jack has walked away from many of his past interests—he left his dissertation in American History unfinished, and never managed to marry his first love, Anne Stanton, the daughter of a former governor of the state.

When Willie asks Jack to look for skeletons in the closet of Judge Irwin, a father figure from Jack's childhood, Jack is forced to confront his ideas concerning consequence, responsibility, and motivation. He discovers that Judge Irwin accepted a bribe, and that Governor Stanton covered it up; the resulting blackmail attempt leads to Judge Irwin's suicide. It also leads to Adam Stanton's decision to accept the position of director of the new hospital Willie is building, and leads Anne to begin an affair with Willie. When Adam learns of the affair, he murders Willie in a rage, and Jack leaves politics forever.

Willie's death and the circumstances in which it occurs force Jack to rethink his desperate belief that no individual can ever be responsible for the consequences of any action within the chaos and tumult of history and time. Jack marries Anne Stanton and begins working on a book about Cass Mastern, the man whose papers he had once tried to use as the source for his failed dissertation in American History.