The Plot Against America is a novel of alternative history which takes place in the 1940s. It is one of Philip Roth's "Roth novels" in which, though it is fiction, the author makes himself and his family the protagonists, rather than use his Zuckerman or Kepesh personas.

The premise of the novel is that in 1940, Charles Lindbergh, the famous aviator, is elected president of the US, ousting Franklin Roosevelt from office. Lindbergh, in Roth's depiction, is openly pro-Nazi and anti-Semitic, as the actual Lindbergh in fact was. The focus of the novel is the reaction of Roth's family and other Jewish people to this situation in which they fear, understandably, that Lindbergh will initiate domestic policies similar to those of Hitler. Though this doesn't quite happen, there are subtle (and sometimes not subtle) changes in the way Jews are treated, including plans to indoctrinate Jewish children with "non-Jewish values" by placing them with Gentile families. There is also a subplot about Roth's cousin who has enlisted in the Canadian army to fight against the Nazis. He is wounded and returns to the US with his leg having been amputated. This can be viewed as a symbol of the damage done to the Jewish community and to the US as a whole by the aberrant events taking place.

Several other subplots involve both historical and fictional characters and events. The (real-life) journalist Walter Winchell, who was Jewish, is depicted as an outspoken opponent of Lindbergh and is assassinated in the novel. In the end, a restoration of actual historical events occurs after Lindbergh's plane disappears and FDR is restored to the presidency. The US is attacked by Japan at Pearl Harbor and then joins the Allies against Germany and Japan as actually occurred in 1941. A speculative explanation of the Lindbergh presidency is offered, premised on the idea that Lindbergh was a victim of blackmail by the Nazis, who are alleged to have been holding his son (the famous Lindbergh baby actually kidnaped and killed) hostage.

The meaning of alternative history stories is that history is not an inevitable process and that anything "could have happened." "Isolationism," partly rooted in anti-Semitism in the "America First" movement, was an actual phenomenon during World War II. The allegation, made by the historical Charles Lindbergh and others, was that there was a "Jewish conspiracy" to force the US into the war in Europe. Roth's novel combines this fact with speculative fiction which is pessimistic in the extreme, but then reverses itself and gives an optimistic conclusion to the story.

The Roth family—Herman, the father; Bess, the mother; Sandy, the elder son; and Phillip, the younger son and narrator—lives in Newark, New Jersey. They support FDR's run for a third term as president, and they are quite distressed when Charles Lindbergh, the famed aviator, wins instead, because he wants to keep the U.S. out of WWII and seems to have a worryingly close relationship with Hitler and the Third Reich. The story follows the family's life as they attempt to navigate a country and world that seem increasingly hostile to Jews: they are openly discriminated against in the nation's capital and kicked out of their hotel room; their older son is relocated in what seems like an attempt to alienate him from his family and indoctrinate him into Christianity; the government attempts to forcibly relocate the entire family; they care for Herman's nephew, Alvin, who returns from the war missing a leg and very despondent; and they ultimately save the son of their former neighbor when his mother, the boy's only living parent, is viciously murdered for her faith. Life for them is not easy, and they become estranged from various relatives who judge their choices; however, they ultimately hold onto their principles and survive the Lindbergh presidency.