My Ántonia begins with a short fictional introduction told by a nameless narrator, who may or may not be the author herself. The narrator tells you about a friend of hers named Jim Burden, a lawyer for one of the transcontinental railroads. The narrator and Jim were friends when they were kids, and they both knew a rather remarkable Bohemian immigrant girl named Ántonia. (Bohemia is a region in what is now the Czech Republic.) The narrator, who is a writer, tells Jim that she wants to write about Ántonia, but feels that Jim, who knew the girl better, is more qualified to do it. So Jim writes a memoir about the girl and calls it "My Ántonia," and the remainder of the novel is this memoir itself.
Jim is ten years old and has recently been orphaned, so he moves from Virginia to Nebraska to live with his grandparents on their farm. On the ride there, Jim is accompanied by a farmhand named Jake Marpole, and hears that an immigrant family from Bohemia is traveling to the same area. Soon after he arrives on his grandparents' farm, Jim meets the Shimerdas, a Bohemian immigrant family, who turn out to be his grandparents' new closest neighbors. The family consists of Mr. Shimerda, who is unhappy in America and homesick for Bohemia; Mrs. Shimerda, who made the family move to America; Ambrosch, the rather mean and selfish oldest son; Ántonia, who is four years older than Jim; and several other children.
Mr. Shimerda asks Jim to teach Ántonia English, and the two children soon become close friends. Jim seems to hold great admiration for Ántonia – he associates her with the vast beauty of the Nebraskan landscape and the determination and will power common to early immigrants in the American West. As the two of them grow up, the exact nature of his feelings for her are not clear, particularly when it comes to the romantic element.
The Shimerda family suffers through a tough winter, as they don't have a lot of money or friends in the new country. Jim's grandparents help out as much as they can, but Mr. Shimerda ends up committing suicide out of despair and homesickness. Ántonia takes over many of her father's responsibilities, helping out her brother Ambrosch in the fields. When Jim goes off to school in town, she can't come with him, as she has to stay at the farm and work to support her family. Jim and Ántonia's friendship becomes more distant at this point; he's upset with her for working like a man out in the fields, and of course he simply doesn't see her around much after he starts school.
By the time Jim is ready for high school, he and his grandparents move off the farm and into the nearby town of Black Hawk, Nebraska. Ántonia's family remains on the farm, but Ántonia ends up moving in with a family in town called the Harlings and working as a cook/helper around the house. She is part of a group of "hired girls," immigrant girls who work and live in town to support their families back on the farm. This group also includes Lena Lingard and their friend Tiny Soderball. Jim spends a lot of time with these girls, though many people in town look down on them as "beneath" the town girls, socially speaking.
Everyone is growing up, and that includes Ántonia, who ends up being rather beautiful. She, Tiny, and Lena get a lot of attention from the boys, especially at the town's Saturday night dances. Jim, as we've come to expect by now, never admits having any feelings for Ántonia. He does lust after Lena, though Ántonia warns him to stay away from her. Finally, Jim goes off to college in Lincoln, Nebraska and leaves the small town of Black Hawk behind. During his second year, Lena shows up, having moved to Lincoln herself to work as a dressmaker. The two of them start dating, much to the ruin of Jim's GPA. But then his tutor, Gaston, gets Jim to move to Harvard with him, and he leaves Lena behind.
When Jim finishes college, he returns to Black Hawk for the summer before law school. He finds that things have not gone well for Ántonia while he was gone. She was engaged to be married to a man who used up her money, got her pregnant, and then ran off before the wedding. Now she is back living on her family's farm and has a child. But she is otherwise unchanged. Jim sees that she is still fiery and proud. He heads off to Law school, promising Ántonia that he'll come back and visit again soon.
But Jim is afraid to go visit Ántonia again because he doesn't want to find her old and broken. When he finally gets the courage to go back, twenty years have passed, and he is a successful New York lawyer. He finds Ántonia on a farm, married, with about a dozen children. She is, of course, older, but unbroken and with the same spirit. The two of them are happy to see each other and talk about how much they meant to each other when they were growing up. Jim even admits to Ántonia's children that he used to be in love with their mother. As he's leaving the farm, Jim decides it was destiny that he and Ántonia were brought together again after all those years apart, and concludes that together they still share "the incommunicable past" (last paragraph).