There is not as much critical commentary on Flowers for Algernon as there is on some other contemporary novels. What criticism does exist has occasionally found fault with the novel on the grounds of sentimentality or predictability, but on the whole, the critical response has been favorable. Critics have also noted the novel's status as a work of science fiction.

Typical of the critical response to Keyes's novel is Mark R. Hillegas' 1966 Saturday Review essay, which ranks Flowers for Algernon with Kurt Vonnegut's Player Piano and Walter M. Miller, Jr.'s A Canticle for Leibowitz as a "work of quality science fiction," although Hillegas finds the novel "considerably less powerful" than Vonnegut's or Miller's novels. Hillegas also notes that Keyes's novel is occasionally "marred by a cliched dialogue or a too predictable description." Nonetheless, he finds that the novel "offers compassionate insight into the situation of the mentally retarded" and is "profoundly moving."

Other contemporary reviews sounded much the same note. Eliot Fremont-Smith, writing in the New York Times in 1966, states that Keyes "has taken the obvious, treated it in a most obvious fashion, and succeeded in creating a tale that is convincing, suspenseful, and touching—all in modest degree, but it is enough." Despite the many potential problems, such as how to convincingly show Charlie as a genius, "the skill shown here is awesome," and "affecting, too—how otherwise explain the tears that come to one's eyes at the novel's end?" Similarly, a reviewer in the Times Literary Supplement finds some of the minor characters "less successfully created" but praises the novel as "a far more intelligent book than the vast majority of 'straight' novels."

What critical attention Flowers from Algernon has received since its original publication has come mostly from scholars discussing the novel as a work of science fiction. In his 1975 book Structural Fabulation: An Essay on Fiction of the Future, Robert Scholes discusses the novel as "minimal SF" that, unlike some works of science fiction, "establishes only one discontinuity between its world and our own"—in other words, the experiment which raises Charlie's intelligence. Scholes finds the novel "beautifully problematic" and asserts that its power derives largely from the fact that the results of the operation are impermanent. While "Keyes has fleshed out his idea with great skill," Scholes also sees the novel as "deficient in artistic integrity" because of its existence as both a short story and a novel.

More recently, the noted British SF writer and critic Brian W. Aldiss, in his 1986 book, Trillion Year Spree: The History of Science Fiction, compares Charlie to the character of Lenny in John Steinbeck's Of Mice and Men. Unlike other critics, Aldiss prefers the original short story to the novel: "This moving story lost something of its power when expanded to novel length." And in his 1990 study, Understanding Contemporary American Science Fiction, Thomas D. Clareson claims that Keyes "revitalized the myth of Frankenstein by introducing a fresh narrative perspective" and combining "Mary Shelley's nameless creature and the crazed scientist into the single figure of Charlie." Clareson further notes that the novel's "narrative perspective" makes it "unique in the science fiction pantheon."