The novel is written episodically and in reverse-chronological order. It consists of fifteen chapters divided in three parts: Part I (1989–1972), Part II (1970–1960), and Part III (1960–1956). Part I is centered on the adult lives of the García sisters; Part II describes their immigration to the United States and their adolescence, and Part III recollects their early childhood on the island, in the Dominican Republic.
The Garcías are one of the Dominican Republic's prominent and wealthy families, tracing their roots back to the Conquistadores. Carlos García, a physician and the head of the family, is the youngest of 35 children his father sired during his lifetime, both in and out of wedlock. Laura, Carlos's wife, also comes from an important family: her father is a factory owner and a diplomat with the United Nations. Many members of the extended family live as neighbours in large houses on an expansive compound with numerous servants. In the early 1950s the García girls are born. Carla, Sandra, Yolanda and Sofía enjoy a happy, protected childhood and are brought up by their parents, aunts and uncles to preserve the family traditions. Their countless cousins serve them as playmates.
The first part of the novel establishes Yolanda at the centre of the story as she narrates the opening and closing chapter: "Antojos" and "The Rudy Elmenhurst Story", respectively. In third person, Yolanda's return to Dominican Republic as an adult is described in the context of a family birthday party and a road trip. Their unity as sisters as "The Four Girls" is introduced in the third chapter, which is a communally narrated. They celebrate Carlos, the patriarch's, birthday, and Sofía introduces her baby son to his grandfather, helping to repair the father and daughter's relationship somewhat. During Sofía's chapter, "The Kiss", it is revealed that Carlos discovered a packet of love letters addressed to his daughter, enraging him and leading to a conflict which ends in Sofía running away to her German lover. A major focus in this section is the romantic relationships between the four sisters and their partners. Sofía is married to a "world-class chemist"; Carla and Sandra are in long-term relationships; and Yolanda is in love with her psychiatrist and has previously broken up with a man named John. Part I closes with "The Rudy Elmenhurst Story", narrated by Yolanda. This describes Yolanda's first real relationship, and the tension between her upbringing and American relationships: "I would never find someone who would understand my particular mix of Catholicism and agnosticism, Hispanic and American styles."
Part II details the family's collective experience of living in the United States as immigrants. The girls first attend a Catholic school in New York and later boarding school, and assimilate fairly well to their new environments, although meeting with a few set-backs along the way. Their time in the US begins with the opening chapter, "A Regular Revolution", and delivers the girls' (collective) opinion that "We didn't feel we had the best the United States had to offer. We had only second-hand stuff, rental houses in one redneck Catholic neighborhood after another". While during their first few months in New York they regularly pray to God that they will soon be able to return to their homeland, they quickly start appreciating the advantages of living in a "free country" so that even being sent back to the Dominican Republic for the summer becomes a form of punishment for them.
A major turning point in the novel comes with Laura's discovery of a bag of Sofía's marijuana, and her subsequent punishment of being removed from her boarding school and forced to spend a year in the Dominican Republic with family. This event is representative of the girls' transformation into Americans and away from the Dominican culture and Laura and Carlos' conflicted relationship with the assimilation. Laura "still did lip service to the old ways", and Carlos makes a point of educating the accents out of the girls, thus showing the tension between the cultures.
Carla becomes the victim of racism in the third chapter, "Trespass", with school boys telling her to "Go back to where you came from, you dirty spic!" Later she is subjected to a child molester who masturbates in his car while pulling up at the curb and talking lecherously to her through the open window. The second part of the novel finishes with the chapter "Floor Show", in which the García family goes to a Spanish restaurant and Sandra witnesses the host's wife amorously attempting to kiss her father on the way to the bathroom. Overall, Part II presents the unexpected aspects of living in the United States and becoming Americans, and explores the tensions that develop with the immigrant experience.
The five chapters in Part III, the concluding section, focus on the García family's early years in the Dominican Republic, and are the most political of the novel.
The first chapter, "The Blood of the Conquistadores", opens with an account of two of Trujillo's agents coming to the family home looking for Carlos. His revolutionary politics and work against the Chapitas made the family a target, and this chapter explicitly details the danger of their situation. The issues in past chapters appear superficial in comparison to the life-or-death nature of the conflicts that the Garcías face earlier in their lives. The family escapes persecution, but is forced to emigrate immediately, establishing their motive for relocating to New York.
The second chapter, "The Human Body", describes what happens to Mundin, Yolanda and Sofia in the dirty shed near the house. Yolanda plays with her boy cousin, Mundin, and in exchange for a Human Body doll and a modeling clay, shows him her genitals. Sofia also follows suit. ' "Go on," Mundin ordered impatiently. Fifi had caught on and lowered her pants and panties to her ankles. I gave my sister a defiant look as I lifted up my cowboy skirt, tucked it under my chin, and yanked my panties down (Alvarez, 235).'
As Part III progresses, the narrative switches to describing their upper-class life on the island, and filling details of the lifestyle the family was born into. The story of the voodoo practicing Haitian family maid is elucidated: she escaped Trujillo's massacre of Haitians and came to work for Laura, although much of her family was not so lucky.
In the last three chapters Carla, Yolanda and Sandra narrate stories from their childhood surrounded by the extended family, and the girls' relationship with the United States begins. "An American Surprise" tells of their early ideas of New York City, "where it was winter and the snow fell from heaven to earth like the Bible's little pieces of manna bread." The reader realizes that the innocence of childhood and idealized vision of their soon-to-be adopted country, given the reverse-chronological narration of How the García Girls Lost Their Accents, are left behind with the García's home in the Dominican Republic.