It is set in the United States in the near future, ravaged by climate change and disease, in which the Second Civil War has broken out over the use of fossil fuels.

In 2074, after the passage of the Sustainable Future Act, a bill in the United States that banned the use of fossil fuels anywhere in the country and was the catalyst for the assassination of the President of the United States in December 2073 in Jackson, Mississippi by a secessionist suicide bomber, Mississippi, Alabama, Georgia, South Carolina, and Texas secede from the Union, starting the Second American Civil War.

South Carolina is quickly incapacitated by a virus released by the U.S. government known as "The Slow," a biological weapon that makes its inhabitants lethargic.

Texas is invaded and occupied by Mexico, and the remaining bloc, known as the "Free Southern States" (Mississippi, Alabama, and Georgia, or "The Mag"), continues to fight.

Her family consists of her parents, Benjamin and Martina; her older brother, Simon; and her fraternal twin sister, Dana Chestnut.

Following the Camp Patience massacre, Sarat and her siblings are resettled by the Free Southern government in Lincolnton, Georgia, on the border with South Carolina.

While Sarat has become a member of Gaines' rebel group, the broken Simon is tended by a Bangladeshi American woman, named Karina.

Benjamin is intrigued by Sarat and realizes that his aunt is still haunted by the attack at Camp Patience, her time as an insurgent, and her torture at Sugarloaf.

Sarat is later visited by Joe, the Bouazizi agent, who recruits her into carrying a deadly virus during the Reunification Ceremony in the U.S. capital of Columbus, Ohio.

Seeking revenge against the U.S. government, Sarat accepts the offer and convinces her former rebel comrades to secure her passage to the Reunification Ceremony.

Decades later, Benjamin discovers his aunt's diaries and learns of her experiences during the Second American Civil War and her role in the Reunification Plague.

Much of the novel is set in the "Free Southern States", which originally consisted of Mississippi, Alabama, Georgia, South Carolina, and Texas.

The conflict started after the assassination of President Ki during a suicide bombing attack in 2073, as well as the shooting of Southern protesters outside Fort Jackson, South Carolina in 2074.

After multiple failed revolutions, the states of Northern Africa and portions of the Arab world and Central Asia have united as the Bouazizi Empire, with their capital in Cairo.

[5] In The New York Times, book critic Michiko Kakutani compared it favorably to Cormac McCarthy's The Road and Philip Roth's novel The Plot Against America.

[10] In November 2019, a panel of six writers, curators and critics selected by the BBC News included American War among a list of 100 novels that have had an impact on their lives.