At the age of ten, Jim Burden travels by cross-country train to live with his grandparents on the Nebraska frontier. He has just recently lost both his parents, and he is accompanied by a farmhand named Jake. On the same train is a Bohemian family that barely speaks English and that is going to the same place. When Jim arrives at the station, he is greeted by Otto Fuchs, an Austrian desperado cowboy.
Jim's grandparents are kindly people with simple religious beliefs and very generous natures. Jim enjoys the wide expanses of the frontier, with all its insects, prairie dogs, and vegetation. At this point in the year it is still summer. Soon the Burdens go to meet their Bohemian neighbors, the Shimerdas, who were forced to pay too much for their farm by the only other Bohemian man in the country, Peter Krajiek. Jim meets Mr. Shimerda, an educated musician who is very kindly; Mrs. Shimerda, a shrewish woman who is complaining and demanding; the oldest son Ambrosch, who is a stubborn, stingy brute; Marek, a mentally challenged boy; and Yulka, a young and pretty girl. The oldest daughter Ántonia also comes running up to him, grabs his hand, and they go sprinting into the fields.
Ántonia and Jim instantly become friends, and they spend a lot of time together outdoors, with Jim teaching her English. The Shimerdas are not doing very well in their new country, but they do become friends with two Russian men, Peter and Pavel. The Burdens try to help out as much as they can. One day during the end of summer, Jim kills a huge snake and impresses Ántonia, who had been treating him with condescension.
Soon, winter comes. Jim gets very sick, and Pavel dies, after unburdening his heart with a horrible story from his past. Mr. Shimerda becomes depressed after Peter moves away. The Burdens celebrate Christmas at home and make presents for each other since they cannot get into town to purchase some. Mr. Shimerda comes to thank the Burdens for his family's gifts and ends up spending the day with them.
In the middle of the biggest snowstorm in ten years, Mr. Shimerda shoots himself after arranging himself neatly in the barn. Jake suspects that Krajiek killed Mr. Shimerda, but nothing is ever proven. The day afterwards, Jim is left in the house by himself, and he senses Mr. Shimerda's spirit resting on his way back to his homeland. The Shimerdas insist that Mr. Shimerda be buried at the corner of their property, where eventually a crossroads will be. The funeral ceremony is very moving though somewhat disorganized.
Afterwards, the Burdens and other neighbors make a concerted effort to help the Shimerdas. Ántonia begins farming in the fields like a man and gives up going to school. Jim is resentful that Ántonia no longer spends as much time with him, and the Burdens and the Shimerdas get into a little feud because of Ambrosch's bad behavior. The Shimerdas do not act very grateful for the help that they receive from their friends. Eventually, however, everyone is reconciled.
After three years in the country, Jim's grandparents move to the town of Black Hawk so that Jim can go to school. Ántonia also comes into town to work for the Harlings in their home. Other immigrant country girls also start working in the town, and they become known as the hired girls. Jim spends a lot of time with Ántonia and the Harling children, who form a happy household. Dancing becomes the craze in Black Hawk, and Ántonia starts going all the time. When the Harlings ask her to stop going because she is getting a bad reputation, Ántonia quits and starts working for Wick Cutter, a notorious philanderer. During this time Jim is antisocial and only spends time with Ántonia and the other hired girls. He studies a lot in preparation for college and wants to leave Black Hawk as soon as possible.
At college in Lincoln, Jim becomes very close to his Latin instructor and mentor Gaston Cleric. They spend a lot of time talking intimately, although Jim realizes that he is not an academic as Gaston is. One day Lena Lingard, one of the hired girls, comes to visit him, and they start going to plays together. They spend a lot of time together, even though two other men in Lena's building are in love with her. Gaston Cleric notices that Jim is being lax in his schoolwork and asks him to follow him to Harvard. Jim agrees and says goodbye to Lena.
Two years later, before entering law school, Jim returns to Black Hawk, where he hears about Ántonia. Apparently Ántonia had gotten pregnant and was engaged to be married to Larry Donovan. She followed him to Denver, but he ran off soon after she arrived. She returned to her family's farm where she had her child, avoided people, and worked the land. Jim goes to visit her and tells her how much she means to him. She is a little surprised that Jim is not disappointed in her. Jim promises to return again to visit.
He doesn't return until twenty years have passed after hearing that Ántonia has gotten married to a man named Anton Cuzak and now has about ten or eleven children. He is a little nervous about seeing how age has affected her. When he arrives on the Cuzak farm, he is greeted by many of her children. Ántonia doesn't immediately recognize him, but is very excited when she does. She shows him all around the farm, which is full of life. There are kids, trees, vegetation, and food everywhere they go, and everyone seems happy and content. Jim is happy to see Ántonia looking so well and sleeps in the barn with two of the boys.
The next day he meets Cuzak, who was away on a small vacation. Jim likes Cuzak immediately and sees that Cuzak and Ántonia's marriage is one of equality and mutual contentment. Cuzak tells Jim how much he loves Ántonia, and the next day Jim leaves. He promises to go hunting with Ántonia's sons and returns to Black Hawk for the day. There he finds the old dirt road that used to go to his grandparents' farm, and he thinks about how that road was the road of Destiny and how now he has returned full circle back to where he started.