Bless Me, Ultima is about the social-psychological maturation of a Mexican-American, or Chicano, boy living on the eastern plains of New Mexico during the 1940s. The novel begins with Ultima, a curandera,or folk healer, going to live with the Márez family during the summer that Antonio is six years old. Antonio is preoccupied with and anxious about attending school and having to be separated from his mother. Related to these concerns is his engrossment with knowing his destiny. This concern is exacerbated by his mother's desire that he become a priest to a community of farmers, where her family lives. At the same time, Antonio is concerned about realizing the wandering desire that stems from his paternal lineage.
Antonio is nearly at the point of starting religious study for his first holy communion and is becoming concerned with good and evil in the world. Early in the novel, he witnesses the killing of Lupito, a war veteran, and fears that his father may be punished by God for being with the men who killed Lupito. Antonio is deeply concerned about the fate of Lupito's soul.
As the novel develops, Antonio's fears and concerns intensify and become woven together as he struggles to understand the events surrounding his life. He becomes preoccupied with questions about his destiny, life and death, and good and evil. Ultima conveys an indigenous viewpoint to him that provides guidance when he loses confidence in parental viewpoints and the teachings of the Church. Ultima tells him the stories and legends of his ancestors, and he comes to understand how the history of his people stirs his blood. Through her, Antonio learns the "old ways" and develops a new relationship with nature. This relationship opens him to the contemplation of the possibility of other gods.
Antonio learns there are powers in the world that differ from those honored by the Catholic faith. He helps Ultima perform a healing that saves the life of his Uncle Lucas, who had been bewitched by the Trementina sisters. Later, he witnesses another healing performed by Ultima and begins to understand the world differently; he learns to overcome his fears, especially his fear of change. In the end, Antonio understands himself and the world around him better, and he learns to accept life and the many challenges that it presents.