The Human Stain is a novel of identity that revolves around the love affair of two people who could not be more opposite. Coleman Silk is a classics professor, a man who was once well respected in his small community before an accusation took from him the identity he spent fifty years creating. Coleman's lover, Faunia Farley, is an illiterate woman who is being stalked by the ex-husband who blames her for the death of their two small children. This love affair creates a scandal in their small town that is only rivaled by President Bill Clinton's relationship with Monica Lewinsky. From award winning author Philip Roth, The Human Stain is a statement on twentieth-century morality that could not have been voiced as well by any other writer.

Coleman Silk was a classics professor at small but prestigious Athena College before an accusation of racial discrimination brought his career to an early end. Coleman Silk is innocent of the charges brought against him, charges, charges which stemmed from the innocent use of a word that once held bigoted connotations, but the investigation ended Coleman's enthusiasm for the work. Not only that, but Coleman's wife suffers a stroke while supporting him during the investigation, leading to her early death that Coleman blames on the college and the investigation. Coleman goes mad with grief, determined to set the record straight. Coleman wants a book to be written about the entire affair and asks his neighbor, Nathan Zuckerman, to write it. When Nathan refuses, Coleman sets about writing the book himself.

However, two years later when the first draft is finished, Coleman no longer has the anger to continue. Coleman has begun an affair with a thirty-four year old woman, a woman more than half his age. This woman, Faunia Farley, is a cleaning woman at the college who has suffered terrible abuse both at the hands of her stepfather and her ex-husband. Faunia also lost her two small children when a fire broke out in her apartment one night while she was occupied with a fight between her ex-husband and her current boyfriend. Faunia tells Coleman she is illiterate and not interested in learning to read. Faunia wants Coleman to understand that all she wants from him and all he should want from her is the sexual part of their relationship. Coleman agrees to this since Faunia reminds him of a woman he once knew in his youth. Coleman feels young again with Faunia, young and free.

Coleman grew up in East Orange, the second son of a well-educated black couple. Coleman's father is an optician who once had his own optical store. However, Coleman's father lost the store to the Great Depression and now he works as a waiter on the Pennsylvania train line. Coleman's mother is a nurse and will be the first black head nurse in a Newark hospital. Coleman's father is a college graduate who encourages his children to learn Latin and Greek as well as study the great works of Shakespeare. It is Mr. Silk's dream to see Coleman go to Howard College.

Coleman attends Howard for a semester, but he does not like it. For the first time in his life Coleman experiences open discrimination and becomes a part of the collective "we" that is a part of attending a school primarily of black people. When Coleman's father dies, he drops out of Howard and enlists in the Navy as a white man. After the Navy, Coleman gets an apartment in New York and enrolls in NYU. Coleman falls in love with a tall girl from the Midwest and is deathly afraid she will learn the truth about his racial heritage. After two years, however, Coleman is ready for her to know so that he can ask her to marry him. The visit seems to go well, but on the ride home the girl tells Coleman she cannot be in a relationship with him and disappears from his life.

After this, Coleman meets a young black girl with whom he can be himself. This girl shows Coleman other men who are passing in the city around them, men Coleman would never have guessed were men of color. This relationship does not last long, however, as Coleman meets Iris, the woman who is destined to be his wife. After what happened when he told his other girl, Coleman makes the conscious choice not to tell Iris about his racial heritage and instead invents a story in which he is an only child and an orphan.

Coleman and Iris have four children together, three boys and a girl with whom Coleman remains close, except for Mark, his youngest son. Mark is a rebellious young man who questions everything Coleman has ever told him. When Lisa, his daughter, refuses to speak to Coleman on the phone during his affair with Faunia, Coleman assumes it is Mark who told her lies about Coleman. However, it turns out that Lisa heard from friends in Athena that Coleman forced Faunia to have an abortion and Faunia attempted suicide as a result. None of this is true.

Faunia's ex-husband, Lester Farley, is a Vietnam Vet who suffers from post-traumatic stress disorder. Lester beat Faunia brutally during their marriage and has stalked her since the divorce. Lester was present the night their children died, watching Faunia sit with her new boyfriend in his truck. Instead of saving the children when he smelled smoke, Lester turned on the boyfriend and tried to kill him. Now he is stalking Faunia and Coleman, going so far as to approach them on Coleman's property.

Friends of Lester take him to the VA for help after he harasses Coleman and Faunia. Another Vet hears Lester's story and tries to help him by first taking him to a Chinese restaurant to help him overcome his fear of Asians and then on a trip to see the Moving Wall to see the names of a buddy of his who died in Vietnam. Lester has difficulty with these therapeutic sessions, resulting in a psychotic break of sorts after visiting the wall. Lester decides he must kill Coleman in order to fix what went wrong between him and his buddy in Vietnam. Lester drives in the wrong lane on a river road to force Coleman's car into the river, unaware that Faunia is in the car with Coleman.

Before Coleman's death, another professor at the college, Delphine Roux, has taken it upon herself to harass and spread lies about Coleman. Delphine was the professor who spearheaded the investigation against Coleman that ended his career. Delphine is possibly behind the abortion rumor about Coleman and Faunia and the author of an anonymous note Coleman received regarding Faunia. The morning after Coleman's death, Delphine offered her final insult by staging a fake break-in and blaming it on Coleman, all to cover the fact that she accidentally sent a personal ad e-mail describing Coleman as the perfect man to all her department colleagues.

After Faunia's funeral, Nathan meets Faunia's father and learns that she was not illiterate as she made everyone believe. After Coleman's funeral, Nathan meets Coleman's sister, Ernestine. Ernestine tells Nathan about Coleman's childhood, of his decision to pass as white, and her older brother Walt's decision to forbid Coleman from contacting the family ever again. Ernestine does not condone Coleman for his choice, however saddened she is that he chose to never tell his children the truth. Ernestine loves Coleman and is the only family member who found a way to keep in contact with him all these years. Ernestine later invites Nathan to her home to meet Walt and his wife. Nathan has decided to write Coleman's book and sees this trip as research into Coleman's past.

On his way to East Orange, Nathan passes by Lester's truck on the side of the road. Lester is ice fishing on a small lake in the middle of nowhere. Nathan talks to him about fishing, asking him leading questions as though he hopes Lester will confess to killing Coleman and Faunia. Instead, Lester makes veiled threats and leaves Nathan with the feeling that when he is done writing his book, he had better get out of town.