The critical reception of Of Mice and Men was the most positive that had greeted any of Steinbeck's works up to that time. The novel was chosen as a Book of the Month Club selection before it was published, and 117,000 copies were sold in advance of the official publication date of February 25,1937. In early April, the book appeared on best-seller lists across the country and continued to be among the top ten best-sellers throughout the year. Praise for the novel came from many notable critics, including Christopher Morley, Carl Van Vechten, Lewis Gannett, Harry Hansen, Heywood Broun, and even from First Lady Eleanor Roosevelt. Henry Seidel wrote in the Saturday Review of Literature that "there has been nothing quite so good of the kind in American writing since Sherwood Anderson's early stories." New York Times critic Ralph Thompson described the novel as a "grand little book, for all its ultimate melodrama."

At the time of the book's publication, critical reaction was mostly positive, although at the end of the 1930s, after Steinbeck had written The Grapes of Wrath, there was some reevaluation of Steinbeck's earlier work. Some critics complained that Of Mice and Men was marred by sentimentality. Other critics faulted Steinbeck for his portrayal of poor, earthy characters. When Steinbeck won the Pulitzer Prize for The Grapes of Wrath, one of his strongest critics, Arthur Mizener, condemned Steinbeck's receipt of the award, faulted the author for his love of primitive characters, and criticized his sentimentality. In 1947, an article by Donald Weeks criticized Steinbeck both for sentimentality and for the crude lives of his characters. Obviously, Steinbeck caused problems for many reviewers and critics, who wrote contradictory attacks on the novelist, alternately blasting him as too sentimental and too earthy and realistic for their tastes.

In addition, Steinbeck had written three novels about migrant labor in California by the end of the 1930s. Many critics at the time dismissed these novels as communist or leftist propaganda. In fact, Steinbeck's work has often been discussed in sociological, rather than literary, terms. This is unfortunate because it misses the author's intentions: whatever politics or sociology are contained in Steinbeck's works are minor elements in novels of great literary merit. After the 1930s, there were several decades of what can only be described as a critical trashing of Steinbeck's work. When the author was awarded the Nobel Prize for Literature in 1962, very few critics praised the choice. Many publications neglected to even cover the event. Writing in the New York Times, Arthur Mizener attacked Steinbeck in an article entitled, "Does a Moral Vision of the Thirties Deserve a Nobel Prize?" The article was published just before the Nobel Prize was presented to Steinbeck in Sweden. The article stated: "After The Grapes of Wrath at the end of the thirties, most serious readers seem to have ceased to read him " He went on to state that the Nobel Committee had made a mistake by bestowing the award on a writer whose "limited talent is, in his best books, watered down by tenth-rate philosophizing." Most of the critical opinion at the time was that Steinbeck's career had seriously declined since 1939. Time and Newsweek did not write favorably of the Nobel Prize to Steinbeck. An editorial in the New York Times went so far as to question the process of selection for the award: "The award of the Nobel Prize for Literature to John Steinbeck will focus attention once again on a writer who, though still in full career, produced his major work more than two decades ago. The...