Although both Jim Burden and Antonia Shimerda are new to Nebraska (they arrive at the same time), Jim is an American who has to leave Virginia after his parents' deaths to live with his grandparents. Antonia has traveled much further: she and her family came as immigrants from Bohemia (now the Czech Republic).

Jim arrives to live in a warm, welcoming home on the prairie, whereas Antonia and her family must live in a sod house after they are conned out of their hard-earned savings by a fellow Czech immigrant. Antonia struggles to survive, but she loves the land, and she and Jim play and grow up together. Jim's grandparents insist on his getting a formal education. He eventually heads to university and pursues a career. Antonia, after the suicide of her father, is forced to work in the fields and eventually becomes a "hired girl" in the town of Black Hawk, where she flourishes, attending dances and becoming a social butterfly.

Jim is a serious young man, while Antonia is more playful and carefree. Jim leaves Black Hawk for good and leads a full academic life. Antonia, however, gets pregnant without a husband. She finally meets a good husband (another Czech) and has many children, living out on the prairie she loves. Jim and Antonia lead different lives, but they continue to see one another from time to time and reminisce about their shared childhood. Antonia seems happy, but Jim expresses regret that Antonia was never his "sweetheart."

One important difference between Jim and Antonia is, of course, that Jim is a member of an established and properous Anglo Protestant family, while Antonia's family are Catholic immigrants from central Europe. Jim's relative privilege compared to the Shimerdas is clear when the Burdens invite the Shimerdas to Christmas dinner. The novel has much to say about class and friendship. Jim and Antonia are friends even though they have very different paths in life marked out for them.

The basis for this friendship however is a shared wonder at the new land they each find themselves in. Jim comes to the Burdens as an orphan, and is essentially as much a stranger to Nebraska as Antonia. Much of the novel is about how Jim and Antonia, despite their differences, explore this new place together.

This connection is what makes Jim and Antonia's friendship so compelling. In a sense, Jim and Antonia share an understanding of their lives on the prairie that transcends their considerable differences. Even though Jim becomes a lawyer, and Antonia goes on to have ten children, the book ends with their coming together a final time. All of Antonia's children know Jim, the hero of their mother's childhood. The memory of what Jim and Antonia shared lives on.