In 2005, Brideshead Revisited was chosen by Time magazine as one of the one hundred best English-language novels from 1923 to present. In various letters, Waugh himself refers to the novel a number of times as his magnum opus; however, in 1950 he wrote to Graham Greene saying "I re-read Brideshead Revisited and was appalled." In Waugh's preface to the 1959 revised edition of Brideshead the author explains the circumstances in which the novel was written, in the six months between December 1943 and June 1944 following a minor parachute accident. He is mildly disparaging of the novel, saying; "It was a bleak period of present privation and threatening disaster — the period of soya beans and Basic English — and in consequence the book is infused with a kind of gluttony, for food and wine, for the splendours of the recent past, and for rhetorical and ornamental language which now, with a full stomach, I find distasteful."

Brideshead Revisited was brought to the screen in 1981 in the ITV drama serialisation, produced by Granada Television. A film adaptation of the book was released in July 2008.

1923: After an unpleasant chance first encounter, protagonist and narrator Charles Ryder, a student at Hertford College, Oxford University, and Lord Sebastian Flyte, the younger son of the aristocratic Marchmain family and himself an undergraduate at Christ Church, become friends. Sebastian takes Charles to his family's palatial home, Brideshead, where Charles eventually meets the rest of Sebastian's family, including his sister Julia.

During the holiday Charles returns home, where he lives with his widower father. Scenes between Charles and his father Ned (Edward) provide some of the best-known comic scenes in the novel. He is called back to Brideshead after Sebastian incurs a minor injury. Sebastian and Charles spend the remainder of the summer together. They form a romantic friendship, possibly become lovers. Waugh writes that Charles had been "in search of love in those days" when he first met Sebastian, finding "that low door in the wall... which opened on an enclosed and enchanted garden", a metaphor that informs the work on a number of levels.

Sebastian's family is Catholic, which influences the Marchmains' lives as well as the content of their conversations, all of which surprises Charles, who had always assumed Christianity to be "without substance or merit". Lord Marchmain had converted from Anglicanism to Catholicism in order to marry his wife but soon abandoned both his marriage and religion to Italy. Left alone, Lady Marchmain focused even more on her faith, which is also very much espoused by her eldest son, Lord Brideshead ("Bridey"), and her youngest daughter, Cordelia. Sebastian, a troubled young man, descends into alcoholism, drifting away from the family over a two-year period. He flees to Morocco, where his drinking ruins his health. He eventually finds some solace as an under-porter/charity case at a Tunisian monastery.

Sebastian's drifting leads to Charles's own estrangement from the Marchmains, yet he is fated to re-encounter the family as the years pass. He marries and fathers two children, but his wife is unfaithful and he eventually forms a relationship with Sebastian's younger sister Julia, who by that time has married but separated from the wealthy but coarse Canadian entrepreneur, Rex Mottram. This marriage was a source of great sorrow to her mother, as Rex, though initially planning to convert to Catholicism, turned out to have divorced a previous wife in Canada and so he and Julia end up marrying in a Protestant church.

Charles and Julia plan to divorce their respective spouses so that they can marry. On the eve of World War II, the aging Lord Marchmain returns to Brideshead to die in his ancestral home. As he names Julia (and not his eldest son Brideshead) heiress to the estate, this would give Charles marital ownership of the house. Lord Marchmain's deathbed return to the faith changes the situation: Julia decides that she cannot enter a sinful marriage with Charles, who too has been moved by Lord Marchmain's reception of the sacraments.

The plot concludes in the early spring of 1943 (or possibly 1944 – the date is disputed). Charles is "homeless, childless, middle-aged and loveless". He has become an army officer after establishing a career as an architectural artist, and finds himself unexpectedly billeted at Brideshead. Charles finds the house damaged by the military occupation but the private chapel, closed after Lady Marchmain's death in 1926, has been reopened for the soldiers' worship. It occurs to him that the chapel (and, by extension, the Church's) builders' efforts were not in vain, even when their purposes may appear, for a time, to be frustrated.

Taking into account the background of the author, the most significant theme of the book is Catholicism. Evelyn Waugh was a convert to Catholicism and the book is considered to be an attempt to express the Catholic faith in secular literary form. Waugh wrote to his literary agent A. D. Peters, "I hope the last conversation with Cordelia gives the theological clue. The whole thing is steeped in theology, but I begin to agree that the theologians won't recognise it." Considering his readership, who were generally urbane and cosmopolitan, a sentimental or a didactic approach would not have worked. Sentimentalism would have cheapened the story while didacticism would have repelled a secular audience through excessive sermonising.

Instead, the book brings the reader, through the narration of the agnostic Charles Ryder, in contact with the severely flawed but deeply Catholic Marchmain family. While many novels of the same era portray Catholics as the flatfooted people put on the spot by brilliant non-believers, Brideshead Revisited turns the table on the agnostic Charles Ryder (and presumably the reader as well) and scrutinises his secular values, which are tacitly portrayed as falling short of the deeper humanity and spirituality of the Catholic faith.