The novel opens in 1933 as Jack Burden, the narrator and chief of staff for Willie Stark, Governor of Louisiana, rides with Stark in a black Cadillac to Mason City, where Stark grew up. Also in the car are Stark’s wife and son, Lucy and Tom, and Stark’s Lt. Governor, a former political rival named Duffy. Stark stops in Mason City, then visits his father on a farm outside town. Journalists following in another car, along with Sadie Burke, Willie’s secretary, ask for photo-ops at the farmhouse with Willie, Lucy, and Tom. Willie obliges. Sadie informs Willie outside, later, that Judge Irwin has endorsed one of Willie’s political opponents for a Senate seat, and Willie announces later that night that he, Jack, and Sugar-Boy, Willie’s driver, will be driving to talk to Irwin in Burden’s Landing, which is several hours away and the town where Jack grew up. Willie attempts to convince Irwin to change his mind and endorse the candidate Willie prefers, but Irwin says no. While leaving, Willie tasks Jack with finding “dirt” on Irwin that he can use as blackmail to make Irwin comply with his (Willie’s) political wishes.
Jack goes on to describe Willie’s rise as a politician in Louisiana. Once a low-level County bureaucrat, Willie was defeated in an election after crusading for fairness and openness in a bidding process to build a schoolhouse. When the schoolhouse crumbles owing to shoddy workmanship, killing several children, Willie is recognized as a politician “for the people,” and is tapped to run by the state’s Democratic Party as a candidate for governor in 1926. Sadie Burke, who works for the Party machine, takes over Willie’s campaign, and Jack covers it as a newspaper reporter for the Chronicle. One night, Jack is in the room on the campaign trail when Sadie admits to Willie that he is actually a "stooge" candidate, chosen by the Democratic Party to split the rural vote with MacMurfee, another rural politician, so that the Democrats favored politician will win. This news causes Willie to start drinking alcohol (he has, till now, abstained), and Willie goes onto the trail decrying Partying politics, saying he will support MacMurfee in 1926, and vowing to return in 1930 as a gubernatorial candidate himself. Willie makes good on this promise and is elected governor in 1930, then to another term in 1934. Willie later hires Jack when the newspaper fires him (for supporting Willie); Jack becomes Willie’s political “jack of all trades.”
Jack goes on to write about Willie’s political career as governor, his hard-handed methods to keep opposition in line, and his fervent desire to help the people of Louisiana by improving schools, roads, and the tax code, and by building a free hospital for all to use. Some of the political “old guard” in the state, including Judge Irwin, Jack’s mother, and Anne and Adam Stanton, Jack’s friends from Burden’s Landing, do not approve of Willie’s methods, and hate that Jack works for him. But Jack supports Willie during a period when the state legislature attempts to impeach Willie for supposed “bribery”—Willie beats the charges by blackmailing state legislators, and Jack considers this a political victory for Willie and his policies.
Jack recalls his life as a graduate student at LSU, when he was working on a doctorate in history and writing about an ancestor of his named Cass Mastern, who died in the Civil War after being involved in a love affair that caused his friend Duncan Trice to kill himself, and his lover Annabelle Trice to flee Kentucky to Washington, D.C. Cass later died in the Civil War. Jack found he was unable to write his dissertation on Mastern, despite knowing the “facts” of Mastern’s life, because Jack felt he could not properly represent the “truth” of these facts. Jack relates this journey of historical research to his newer task—that of trying to find “dirt” on Judge Irwin. Jack eventually succeeds in linking Irwin to a bribe Irwin accepted from the American Power company long ago, via communication with a woman named Lily Littlepaugh, whose brother Mortimer was fired so that Irwin could take his position at the American Power corporation.
Willie, in the meantime, wants Adam to run his free hospital, despite Adam’s objection, and Willie uses this information about Irwin and Adam’s father, Governor Stanton (who looked the other way while the bribe happened) to show Adam that all politicians, including the Stantons, must use backhanded tactics to get what they want. Adam begrudgingly accepts the job to head Willie’s hospital. But Jack later learns that Anne, who once opposed Willie, has been having an affair with him—Jack confirms this with Anne and drives from Louisiana to California to clear his head.
Jack is so devastated by Anne’s revelation of the affair because he, Jack, was once engaged to Anne back in Burden’s Landing, though they drifted apart and Jack later married, and divorced, a woman named Lois. Jack returns to Baton Rouge after several days and admits to thinking that all life is nothing more, now, than a Great Twitch, a series of responses to stimuli, since Anne, the love of his life, has decided to take up with another man and leave Jack in the dust.
The novel approaches its end as Jack reveals that Tom, Wilie’s only son, is injured severely in a football game; Tom is paralyzed from the neck down, and Willie is receiving political pressure from MacMurfee and the father of a woman named Sibyl to give up his Senate aspirations, since Sibyl reports she is having a child by Tom. Willie can’t stand this blackmail and attempts to get Jack to convince Irwin to put pressure on MacMurfee, by using Irwin’s “dirt” against him; but Irwin kills himself after meeting with Jack, and Jack’s mother reveals that Irwin was secretly Jack’s biological father.
This means Willie cannot use leverage with Irwin to force his hand and defeat his political enemies—he must instead accept Gummy Larson (a Democratic Party strongman) and Duffy’s back-room deal for the hospital, which devastates Willie, who had wanted the creation of the hospital to be clean of any political graft. After Tom’s injury, however, Willie reneges on his deal with Gummy and Duffy. Sadie, angry with Willie about his affair with Anne, convinces Duffy to tell Adam of the affair, knowing that Adam will want to harm Willie, and this indeed comes to pass—Adam shoots and seriously injures Willie in the capitol before he himself is killed.
Willie dies several days later, and Jack reports that, after discovering that Sadie and Duffy were behind the crime, Jack moves back to Burden’s Landing, since he has taken over Irwin’s house, and he and Anne live there with the “Scholarly Attorney,” the man whom Jack had thought was his father before the revelation that Irwin was his real father. Jack reports that he has written the story of Willie’s life and his own, and now he must write the story of Cass Mastern in order to investigate fully the nature of time, regret, and the past on his own life. The novel ends.