Fire and Blood is set within the same universe as George R. R. Martin's famous A Song of Ice and Fire and covers the history of the Targaryen dynasty (allegedly as recorded by a maester), beginning with Aegon's Conquest and running chronologically to the ascension of Aegon III. Thus, this book only covers roughly the first half of the Targaryen dynasty and does not discuss later events, such as the Blackfyre Rebellions or the rebellion of Robert Baratheon, the events which precede A Song of Ice and Fire.

The book is largely subdivided in terms of the various kings (as a history, it's largely a chronicle). Thus, it begins with the Aegon the Conquerer, covering the conquest of Westeros, the attempted conquest of Dorne, and then his years of kingship. From here, Martin discusses the troubled succession and the rise and fall of the tyrannical Maegor (Aegon's son with his sister-wife Visenya), who defeated his own half-brother to take the throne, before shifting focus to Jaehaerys I, regarded as one of the greatest among the Targaryen monarchs. He would in turn be succeeded by his grandson Viserys Targaryen, who would declare his daughter, Rhaenyra Targaryen, his heir and later take a second wife in Queen Alicent. This would set up the events of the so-called "Dance of Dragons," by which Rhaenyra Targaryen (his daughter from his first marriage) would be opposed by Aegon (his first son with Alicent) in a civil war. The marriage between Rhaenyra's son, the future King Aegon III, to Jaehaera (herself a daughter to Aegon II), would bring an end to this period of civil war.

This story is primarily told as a political history, but interwoven with it are various stories of notable personalities. One which stands out is that of Elissa Farman, with her intense desire to explore the larger world beyond Westeros and her theft of the dragon eggs in order to finance it. A second which stands out is the story of Rhaena's theft of Balerion, greatest of the Targaryen dragons, and the gruesome consequences of that moment (along with the unanswered mystery of just what had happened to her and Balerion in whatever place they had disappeared to). We learn more about the personalities and personal stories of these various historical figures of Westeros, in often quite vivid detail.