Set in Southern California during the years following the American conquest of the former Mexican territory, the novel portrays the intertwined fates of a young woman of mixed Indian and Scottish heritage, the powerful Mexican family that raised her, and the Indian man she loves, against the backdrop of the systematic dispossession of California's Indian peoples.
The story opens at sheep-shearing time on the ranch of Señora Gonzaga Moreno, an imperious, deeply Catholic widow who secretly controls every decision on the estate while allowing her beloved eldest son, Felipe, to appear as its head. The shearing has been delayed because Felipe has been ill and because the Señora insists on waiting for Father Salvierderra, an elderly Franciscan monk who visits annually. She demands only Indian shearers from Temecula, led by the young captain Alessandro, son of the respected chief Pablo Assis. The Moreno estate, once vast, has been drastically reduced by the United States Land Commission, which disallowed many of the family's land claims after the American conquest. The Señora's husband, General Moreno, died fighting the Americans, and she has hardened into a stern figure consumed by devotion to her son, her faith, and her hatred of the settlers.
Ramona, the Señora's foster-daughter, is beloved by everyone on the ranch except the Señora, who has never loved her and has kept the secret of her origins. Ramona's father, a Scotsman named Angus Phail, married an Indian woman and entrusted their infant daughter to the childless Señora Ortegna, who loved the child. Before dying, Señora Ortegna gave Ramona into Señora Moreno's care along with jewels and instructions that Ramona was to receive them if she married worthily and with the Señora's approval; otherwise, everything would go to the Church. The Señora accepted this trust reluctantly, seeing the girl as a reminder of scandal. Now 19, Ramona is gentle and joyous, dimly conscious of the Señora's coldness but accepting it without bitterness. Felipe loves her deeply, at first as a sister and then with growing romantic feeling, though Ramona's steady, sisterly manner keeps him from speaking.
When the band of Indian shearers arrives, their leader Alessandro catches sight of Ramona at the brook and is transfixed. The shearing begins, but Felipe collapses from overexertion and Alessandro rescues him. Felipe's fever returns dangerously, and only Alessandro's singing soothes him. Father Salvierderra asks Alessandro to stay as a temporary replacement for Juan Canito, the head shepherd, who has broken his leg. Ramona adds her plea, and Alessandro agrees.
As weeks pass, Alessandro earns the household's trust while his love for Ramona intensifies. Felipe, convalescing on the veranda, observes the growing bond between them and gradually accepts that Ramona sees him only as a brother. Margarita, Ramona's closest maid, who had flirted with Alessandro the previous year, grows jealous and watches the pair with resentment.
The crisis erupts when the Señora discovers Ramona and Alessandro in each other's arms by the willows, where they have just confessed their love. She strikes Ramona and locks her in her room. The next morning, Ramona calmly declares she and Alessandro intend to marry. The Señora forbids it and reveals that Ramona's mother was an Indian. Far from being devastated, Ramona is glad, declaring she is one of Alessandro's people. She refuses the Ortegna jewels, keeping only a crimson handkerchief that belonged to her father. Felipe attempts to mediate, but the Señora maneuvers him into a strategy of passive resistance designed to drive Ramona away.
Alessandro, sent to Temecula for a few days, does not return for 18. When Ramona finds him at last, he is emaciated and grief-stricken: The Temecula Indians have been driven from their village by Americans armed with legal papers. His father, Pablo, went mad from the shock and died. Their livestock was seized. Alessandro believes he has nothing to offer, but Ramona insists on going with him.
That night, Ramona packs essentials, retrieves her horse Baba, leaves a farewell note for Felipe, and slips away with Alessandro into the darkness. She tells him she is Indian, and they agree she will be known henceforth as Majella, meaning "wood-dove." After traveling through the devastated remains of Temecula, they ride to San Diego, where Father Gaspara marries them. Ramona gives her name as Majella Phail, which the priest misrecords, making it impossible for anyone searching for Ramona to find her.
They settle in the Indian village of San Pasquale, where Alessandro's cousin Ysidro is head man. They build a small adobe house, plant wheat, and enjoy a brief period of peace. A daughter is born, called Eyes of the Sky. But American settlers soon claim the surrounding land through legal filings that override the old Mexican decrees. When an American arrives with papers for Alessandro's own plot, he sells his house and crop for $200, and the family flees toward San Jacinto Mountain.
A violent snowstorm nearly kills them, but they are rescued by the Hyer family from Tennessee, including Jeff Hyer's wife, Aunt Ri, whose prejudice against Indians dissolves as she witnesses the couple's dignity. They settle in the village of Saboba, but their daughter, weakened since the storm, grows steadily worse. The government doctor refuses to travel to see the child, and she dies on the journey to reach him. Alessandro's grief drives him toward a mental health crisis. White settlers harass Ramona, and the family retreats to a hidden valley high on San Jacinto, where a second daughter is born.
Alessandro's condition worsens. He suffers episodes of confused wandering, sometimes riding off on strangers' horses believing them to be his own. One day he rides home on a horse belonging to Jim Farrar, a local white man. Before he can return it, Farrar tracks him to the mountain and shoots him dead without waiting for explanation. Ramona covers Alessandro's body with a white altar-cloth, takes her baby, and runs to the nearby Cahuilla village for help. She collapses into delirium.
Felipe, who has spent years searching fruitlessly for Ramona, finds her at last after spotting Baba on a San Bernardino street. Aunt Ri brews a wild wormwood infusion that breaks Ramona's fever. Felipe tells her the Señora is dead and that he needs Ramona to care for him, giving her a reason to live. Farrar is never punished: He claimed self-defense and was released, as no jury would have convicted a white man of killing an Indian.
During the years of Ramona's absence, the Señora had fallen ill and died, revealing on her deathbed the Ortegna jewels she had concealed. Felipe now restores them to Ramona. Life at the ranch is outwardly serene, but Ramona speaks of Alessandro as if he were still present, dwelling in a realm Felipe cannot enter. Dissatisfied with American California's injustice, Felipe proposes they move to Mexico. Ramona eagerly agrees, wanting to spare her daughter from racial prejudice. In Monterey, on the eve of their departure, Felipe confesses his love. Ramona tells him honestly that part of her heart is dead, but she agrees to be his wife. They marry in Mexico City. Sons and daughters follow, but the most beautiful and beloved remains the eldest: Ramona, daughter of Alessandro the Indian.