Cather's fourth novel, and her third to be set in the West, My Ántonia drew attention as the work of an already established writer. In The Borzoi 1920, H. L. Mencken enthusiastically called Cather extraordinary. "I know of no novel that makes the remote fold of the western farmlands more real than My Ántonia and I know of none that makes them seem better worth knowing." The nucleus of subsequent discussions over who is the protagonist can be detected in early reviews. The Nation critic declared the novel the "portrait of a woman," as did other observers; however, some reviewers thought Ántonia no more important than the physical background of the story. Perhaps the best all-around contemporary estimate of My Ántonia is Randolph Bourne's, who recognized in it the realist's command of material, knowledge of the countryside, and understanding of its people. He praised the "gold charm" of its style. In his Dial review, he defined Jim's vision as "romantic" and Ántonia as the "imaginative center" of his memoir. Within this book, he claimed, Cather "has taken herself out of the rank of provincial writers" and given readers a modern, universal interpretation of the spirit of youth. The feeling that Cather had arrived with My Ántonia was shared by Carl Van Doren, who, three years after the novel came out, distinguished her work from that of local colorist Sarah Orne Jewett, whose The Country of the Pointed Firs had been a major influence on Cather. However, troubled by the novel's structural irregularities, or what he felt to be the "largely superfluous" introduction, he admonished her in a Nation article "to find the precise form for the representation of a memorable character." He added that it is not enough merely to free oneself "from the bondage of 'plot.'" One critic compared Cather to English novelist Thomas Hardy in making setting epic in scope and integral to story.

My Ántonia remained a benchmark for Cather but earned her very little money. The World War I novel that followed, however, One of Ours (1922) was not only a best seller, but also earned Cather the Pulitzer Prize. Ironically, the critics were not impressed, and some were outright derisive. During the 1920s and 1930s, Cather was often criticized for retreating from the present to the romanticized past. In a 1933 English Journal article, Marxist critic Granville Hicks continued to praise My Ántonia as a "faithful re-creation" of the "bleakness and cruelty" of prairie monotony and small-town narrowness, but condemned Cather for turning to a remote world in Death Comes for the Archbishop (1927). Alfred Kazin gave faint praise in his 1942 study On Native Ground, saying Cather could "secede with dignity" from modern America by using nostalgia to create values. The explosion of criticism that followed Cather's death in 1947 was more focused on textual problems in My Ántonia and, again, the issue has been raised as to who is the real protagonist. Maxwell Geismar detected a split between the "ostensible heroine, Ántonia" and Lena Lingard, "who almost runs away with the show." For those who saw Ántonia as the main character, the structure of the book became a problem. British critic David Daiches, in his 1951 book-length study of Cather, is typical in this regard. He faults the author for occasionally losing sight of her theme, which he conceives to be the "development and self-discovery of the heroine." E. K. Brown notes in his 1953 critical biography that Cather's strategy of having a male narrator fascinated with Ántonia but remaining detached results in an emptiness at the novel's center.

Richard Giannone's 1968 study Music in Willa Cather's Fiction suggests a different center. Because Ántonia's joie de vivre cannot be conveyed in words, it is "more a rhythm than a reason" and is expressed through music. Giannone puts the d'Arnault episode at the "pulsating center," prepared for by musical references in the first book and then in the scenes at the Harlings', and followed by the "infamous" dances and the playing of Mr. Shimerda's violin at the end. John Randall claimed in his 1960 book The Landscape and the Looking Glass that Cather balances two protagonists; he sees the novel as a system of contrasts: head (Jim) and heart (Ántonia), past (Jim) and future (Ántonia), contemplative life (Jim) and active life (Ántonia), town life (Jim) and country life (Ántonia); also, there are contrasts between life and death, warmth and cold, and order and chaos. Randall also notes Jim's significant crisis in moving from his original family in Virginia to his second one. Similarly psychological in approach, Terence Martin views the novel in his PMLA article in terms of Jim's conflicting impulses toward Lena and Ántonia, between forgetfulness and remembering. He sees Jim as defining both theme and structure, and the novel as presenting his story, not Ántonia's. It is a drama of memory, of "how he has come to see Ántonia as the epitome of all he has valued."

The tendency among recent critics of My Ántonia is to dislodge it from its niche as a work of country-life optimism by exploring undercurrents of death, violence, and sex. In a 1967 Western American Literature article, Charles linked Jim to Mr. Shimerda as a Thanatos (Death) character, arguing that they provide a dark frame for the vibrant story of Ántonia's Eros (Love) nature. However, Susan J. Rosowski, in her 1986 book-length study of Cather, sees My Ántonia as defying analysis, as "a continuously changing work" in the Wordsworthian tradition, a successful balancing of the world of ideas and the world of experience through imaginative fusion. In this interpretation Jim becomes a reacting mind and Ántonia is the object.