Roth delves into the complexities of the human experience, frequently proposing that life is fundamentally irrational. In American Pastoral, for example, Seymour "Swede" Levov, who epitomizes decency and conformity, comes to realize this difficult reality.

The Human Stain explores a question that has intrigued poets for centuries: How do you truly understand who you are? This Sophoclean exploration considers the impact of either being unaware of or denying one's identity. At the heart of this theme is the significance of recognizing and accepting one's parents. The effects of a parent disowning a child, or vice versa, are profound for both the individual and society. When Coleman disowns his mother because she is black, Roth creates one of the most poignant and emotionally intense scenes in his work. This act of denial signifies the deepest emotional divide possible between a parent and child. By rejecting his mother, Coleman paradoxically rejects his own ethnic and cultural roots, cutting ties with his family to "pass" as a Jew. For Coleman, this involves passing as "white" to avoid the consequences of being black in a racially prejudiced, post-World War II America.

An enduring theme in this novel is the effect of war on both individuals and society. This theme, which is closely linked to the previously discussed social issues, is personified in the character of Lester Farley, a Vietnam War veteran dealing with post-traumatic stress disorder. Some scholars suggest that Odysseus may have faced a similar disorder, resulting in his decade-long exile before he could return to Ithaca. Although Farley is supposedly "cured" by his counselors, much like Odysseus is healed during his time away, Farley still exacts harsh "vengeance" on his community upon his return, as he attempts to reclaim his place within his family and society. It seems that neither veteran has fully overcome the "war sickness."

The novel intertwines numerous classical allusions. Athena, the Greek goddess known for her wisdom, was the guardian and supporter of Odysseus. Yet, she deserted him for ten years after he and his followers violated her shrine following the fall of Troy. Athena is seemingly the "patron" of Athena College, but, as the embodiment of wisdom, she has distanced herself from the college where Coleman Silk once served as a classics professor and later as the dean of faculty.

Crossroads symbolize crucial actions and choices in classical literature. For example, Oedipus encountered and killed a grumpy old man at a remote crossroads, only to later realize that the man was his father. The rural crossroads post office, which Faunia Farley cleans twice a week, is where Coleman first encounters Faunia. This ancient myth explores the complexities of human nature and self-awareness, themes that continue in Roth's story. As Sophocles observed, only through bloodshed and exile can a community rid itself of the stains of patricide and incest. Roth skillfully integrates this timeless theme, encouraging readers to consider the ancient Greek story in a contemporary setting.

The novel explores various themes connected to social issues. It illustrates how noble ideals can become tainted when applied excessively or without wisdom. By highlighting the absence of the classical "middle way," the story suggests this balanced approach as the best route to a fulfilling life. The narrative clearly demonstrates the repercussions of crossing boundaries and borders, which often arise from the characters' decisions. As in many well-crafted novels, the physical setting in The Human Stain underscores the mysterious nature of borders.

The title of the novel brings forth another theme: What characterizes human nature? What makes up the "human stain"? What is truly permanent? Is it sexuality, arrogance, fury, or prejudice? Or is racism merely a consequence of pride, sexual longing, and territorial instincts? Furthermore, the theme of Jewish and Black individuals, both portrayed as outsiders and drifters in a primarily white, Anglo-Christian American setting, is examined.