The epic begins with Meghann "Meggie" Cleary, a four-year-old girl living in New Zealand in the early twentieth century, the only daughter of Paddy, an Irish farm labourer, and Fee, his harassed but aristocratic wife. Although Meggie is a beautiful child with curly red-gold hair, she receives little coddling and must struggle to hold her own against her numerous older brothers. Of these brothers, her favourite is the eldest, Frank, a rebellious young man who is unwillingly preparing himself for the blacksmith's trade. He is much shorter than his brothers, but very strong; also, unlike the other Clearys, he has black hair and eyes.
Paddy is poor, but has a wealthy sister, Mary Carson, who lives in Australia on an enormous sheep station called Drogheda. One day, Paddy receives a letter from Mary offering him a job on her estate, Drogheda.
In Drogheda, Meggie meets Ralph de Bricassart, a young, capable, and ambitious priest who, as punishment for insulting a bishop, has been relegated to a remote parish in the town of Gillanbone, near Drogheda. Ralph has befriended Mary, hoping a hefty enough bequest from her to the Catholic Church might liberate him from his exile. Ralph is strikingly handsome, "a beautiful man"; Mary, who does not bother to conceal her desire for him, often goes to great lengths to see if he can be induced to break his vows. Ralph blandly shrugs off these attentions and continues his visits. Meanwhile, he cares for all the Clearys and soon learns to cherish beautiful but forlorn little Meggie. Meggie, in return, makes Ralph the centre of her life.
Frank's relationship with his father, Paddy, has never been peaceful. The two vie for Fee's attention, and Frank resents the many pregnancies Paddy makes her endure. One day, after Fee, now in her forties, reveals she is again pregnant, the two men quarrel violently and Paddy blurts out the truth about Frank: he is not Paddy's biological son. Long ago, Fee had been the adored only daughter of a prominent citizen. Then she had an affair with a married politician, and the result, Frank, was already eighteen months old when her mortified father married her off to Paddy. Because he resembles her lost love, Fee has always loved Frank more than her other children. To the sorrow of Meggie and Fee, when Frank learns that Paddy is only his stepfather, he runs away to become a prizefighter. Fee later gives birth to twin boys, James and Patrick (Jims and Patsy), but shows little interest in them. Shortly afterward, Meggie's beloved little brother, Hal, dies.
With Frank gone and Hal dead, Meggie clings to Ralph more than ever. This goes largely unnoticed because Ralph has now been her mentor for several years; however, as she ripens into womanhood, some begin to question their close relationship, including Ralph and Meggie themselves. Mary Carson has also noticed their changing relationship, and from motives of jealousy mingled with Machiavellian cruelty, she devises a plan to separate Ralph from Meggie by tempting him with his heart's desire: a high place in the Church hierarchy. Although her will of record leaves the bulk of her estate to Paddy, she quietly writes a new one, making the Roman Catholic Church the main beneficiary and Ralph the executor.
In the new will, the true magnitude of Mary's wealth is finally revealed. Drogheda is not the centre of her fortune as Ralph and Paddy have long believed but is merely a hobby, a diversion from her true financial interests. Mary's wealth is derived from a vast multi-national financial empire worth over thirteen million pounds (about A$200 million in modern terms). The sheer size of Mary's bequest will virtually guarantee Ralph's rapid rise in the church. She also makes sure that after she dies only Ralph, at first, will know of the new will– forcing him to choose between Meggie and his own ambition. She also provides for her disinherited brother, promising him and all his grandchildren a home on Drogheda as long as any of them live.
At Mary's seventy-fifth birthday party, Ralph goes to great lengths to avoid Meggie, now seventeen and dressed in a beautiful rose-pink evening gown; later, he explains that others might not see his attention as innocent. Mary dies in the night. Ralph duly learns of the new will. He sees at once the subtle genius of Mary's plan and, although he weeps and calls her "a disgusting old spider" he takes the new will to her lawyer without delay. The lawyer, scandalised, urges Ralph to destroy the will, but to no avail. The bequest of thirteen million pounds works its expected magic, and Ralph soon leaves to begin his rapid advance in the Church.
Before he leaves, Meggie confesses her love for him; after the birthday party, Ralph finds her crying in the family cemetery and they share a passionate kiss, but Ralph refuses her because of his duties as a priest and begs Meggie to find a suitable partner. The Clearys learn that Frank has been convicted of murder after killing someone in a fight. He spends three decades in prison.
Paddy and his son Stuart are killed; Paddy dies in a lightning fire, and Stu is killed by a wild boar shortly after finding his father's body. Meanwhile, Ralph, unaware of Paddy and Stu's deaths, is on his way to Drogheda and suffers minor injuries when his plane bogs in the mud. As Meggie tends his wounds, she tries to seduce him and is rebuffed. Ralph remains at Drogheda only long enough to conduct the funerals.
Three years later, a new ranch worker named Luke O'Neill begins to court Meggie. Although his motives are more mercenary than romantic, she marries him because he looks a little bit like Ralph, but mainly because he is not Catholic and wants little to do with religion-her own way of getting back at Ralph. She soon realises her mistake. After a brief honeymoon, Luke, a skinflint who regards women as sex objects and prefers the company of men, finds Meggie a live-in job with a kindly couple, the Muellers, and leaves to join a gang of itinerant sugarcane cutters in North Queensland. Before he leaves, he appropriates all Meggie's savings and arranges to have her wages paid directly to him. He tells her he is saving money to buy a homestead; however, he quickly becomes obsessed with the competitive toil of cane-cutting and has no real intention of giving it up. Hoping to change Luke's ambition and settle him down, Meggie deliberately thwarts his usual contraception and bears Luke a red-haired daughter, Justine. The new baby, however, makes little impression on Luke.
Father Ralph visits Meggie during her difficult labour; he has come to say goodbye, as he is leaving Australia for Rome. He sees Meggie's unhappiness for himself, and pities her. Justine proves to be a fractious baby, so the Muellers send Meggie to an isolated island resort for a rest. Father Ralph returns to Australia, learns of Meggie's whereabouts from Anne Mueller, and joins her for several days. There, at last, the lovers consummate their passion, and Ralph realises that despite his ambition to be the perfect priest, his desire for Meggie makes him a man like other men. Father Ralph returns to the Church, and Meggie, pregnant with Ralph's child, decides to separate from Luke. She tells Luke what she really thinks of him, and returns to Drogheda, leaving him to his cane-cutting.
Back home, she gives birth to a beautiful boy whom she names Dane. Fee, who has had experience in such matters, notices Dane's resemblance to Ralph as soon as he is born. The relationship between Meggie and Fee takes a turn for the better. Justine grows into an independent, keenly intelligent girl who loves her brother dearly; however, she has little use for anyone else, and calmly rebuffs Meggie's overtures of motherly affection. None of Meggie's other surviving brothers ever marry, and Drogheda gradually becomes a place filled with old people.
Ralph visits Drogheda after a long absence and meets Dane for the first time; and although he finds himself strangely drawn to the boy, he fails to recognize that they are father and son. Dane grows up and decides, to Meggie's dismay, to become a priest. Fee tells Meggie that what she stole from God, she must now give back. Justine, meanwhile, decides to become an actress and leaves Australia to seek her dream in England. Ralph, now a Cardinal, becomes a mentor to Dane, but still blinds himself to the fact that the young man is his own son. Dane is also unaware of their true relationship. Ralph takes great care of him, and because of their resemblance people mistake them for uncle and nephew. Ralph and Dane encourage the rumour. Justine and her brother remain close, although he is often shocked at her sexual adventures and free-wheeling lifestyle. She befriends Rainer Hartheim, a German politician who is a great friend of both Dane and Ralph– unbeknown to her, he falls deeply in love with her. Their friendship becomes the most important in her life, and is on the verge of becoming something more when tragedy strikes.
Dane, who has just become a priest, is vacationing in Greece. While there, he goes swimming one day and dies while rescuing two women from a dangerous current. Meggie reveals before Dane's funeral that Dane is Ralph's son. Ralph dies in Meggie's arms after the funeral.
Justine breaks off all communications with Rainer and falls into a depressed, hum-drum existence. Eventually, they renew their acquaintance on strictly platonic terms, until Rainer visits Drogheda alone in order to urge Meggie to help him pursue Justine's hand in marriage. Justine, now the sole surviving grandchild of Fee and Paddy Cleary, finally accepts her true feelings for Rainer. They marry, but have no plans to live on Drogheda.
The book's title obliquely refers to the mythical "thornbird" that searches for thorn trees from the day it is hatched. When it finds the perfect thorn, it impales itself, and sings the most beautiful song ever heard as it dies. It directly alludes to the Parable of the Sower in the Synoptic Gospels and chapter 9 of the Gospel of Thomas.