The Thorn Birds is a sweeping love story set on Drogheda, a sheep station in the Australian Outback. At its heart is the ill-fated romance of beautiful Meggie Cleary and the handsome Roman Catholic priest, Father Ralph de Bricassart. Forced to choose between the woman he loves, and the Church he is sworn to, Father Ralph's ambitions win, and he stays with the Church, eventually becoming a Cardinal in Rome. De Bricassart never realizes that Meggie's bright, compliant young son, Dane, is his child, even when the boy comes to Rome to study for the priesthood. After Dane's tragic death, Meggie must choose between her own comfort, and the independence of her beautiful, willful daughter Justine, a talented actress. McCullough's tome, almost 700 pages in length, details the private lives of three generations of the Cleary clan over 55 years, and paints a convincing portrait of the trials and rewards of life in the Australian desert, and one woman's doomed love for an unavailable man.

Meggie Cleary is a beautiful, but lonely little girl of nine with red-gold hair, when the family moves to Drogheda. Meggie's brothers are all busy with the ranch, and she is soon forced to quit school to care of the younger children. Ralph de Bricassart, a handsome young Roman Catholic priest, befriends the child. As Meggie grows into a beautiful young woman, the two fall in love, culminating in a kiss after a ball, when Meggie is 16 years old. Mary Carson, the clan matriarch, is jealous and ends the romance by bequeathing the enormous sheep ranch to the Roman Catholic Church, ensuring that De Bricassart will be elevated to bishop, far from Drogheda.

Heartbroken, Meggie marries Luke O'Neill, a man who looks like De Bricassart, and moves to Queensland. Meggie's husband has no interest in living with her, and travels around the countryside cutting sugar cane, forcing Meggie to work as a servant for a Queensland couple, Anne and Ludwig Mueller. During one of Luke O'Neill's rare conjugal visits, they conceive their daughter, Justine. Exhausted, and realizing her marriage is not viable, Meggie retreats to the honeymoon resort of Matlock alone, to sort out her future. Anne Mueller sends de Bricassart to join her, and the two conceive a son during a weeklong idyll. Meggie immediately realizes she is pregnant, and contrives to have sex with her husband, so the child will not be nameless. De Bricassart is transferred to Rome, and does not learn that he has fathered a son, until the boy is grown.

Meggie returns to Drogheda, where Justine grows into a fey, willful young woman, and her brother Dane becomes a sunny child. When Dane decides to become a priest, he travels to Rome to study under De Bricassart's tutelage. Meggie refuses to attend young Dane's ordination in Rome, feeling the Church has taken back the little happiness she stole from it. Just weeks later, Dane dies in Greece, while rescuing a drowning woman. Heartbroken, Justine decides to leave her acting career and lover in London and return to Drogheda. In an act of unselfish love, Meggie insists Justine must continue her own life in Europe, rather than submerging herself in Drogheda, as generations of Cleary women before her have done. The title of the novel is drawn from the legend of a bird that sings just once in its life, more sweetly than any other, but only at the cost of great pain. The title symbolizes the tenderness of the brief, forbidden love affair between Meggie and Father Ralph, resulting in pain and tragedy.