John Howard Griffin, the author and main character of Black Like Me, is a middle-aged white man living in Mansfield, Texas in 1959. Deeply committed to the cause of racial justice and frustrated by his inability as a white man to understand the black experience, Griffin decides to take a radical step: he decides to undergo medical treatment to change the color of his skin and temporarily become a black man. After securing the support of his wife and of George Levitan, the editor of a black-oriented magazine called Sepia which will fund Griffin's experience in return for an article about it, Griffin sets out for New Orleans to begin his life as a black man. He finds a contact in the black community, a soft-spoken, articulate shoe-shiner named Sterling Williams, and begins a dermatological regimen of exposure to ultraviolet light, oral medication, and skin dyes. Eventually, Griffin looks in the mirror and sees a black man looking back. He briefly panics, feeling that he has lost his identity, and then he sets out to explore the black community.
Griffin expects to find prejudice, oppression, and hardship, but he is shocked at the extent of it: everywhere he goes, he experiences difficulties and insults. The word "nigger" seems to echo from every street corner. It is impossible to find a job, or even a restroom that blacks are allowed to use. Clerks refuse to cash his checks, and a white bully nearly attacks him before he chases the man away. After several traumatic days in New Orleans, Griffin decides to travel into the Deep South of Mississippi and Alabama, which are reputed to be even worse for blacks. (In Mississippi, a grand jury has just refused to indict a lynch mob that murdered a black man before he could stand trial.) In Mississippi, he is disheartened and exhausted, so he calls a white friend named P.D. East, a newspaperman who is ferociously opposed to racism. He spends a day with East, during which time they discuss the way racial prejudice has been incorporated into the South's legal code by bigoted writers and politicians. Eventually, a rejuvenated Griffin leaves for a long hitchhiking trip throughout Alabama and Mississippi.
In general, Griffin finds that conditions for blacks are appalling, and that black communities seem run-down and defeated. He even notices a look of defeat and hopelessness on his own face, after only a few weeks as a black man. In Montgomery, however, the black community is charged with determination and energy by the example of one of its leaders, a preacher named Marin Luther King, Jr. Blacks in Montgomery have begun practicing passive resistance, a nonviolent form of refusing to comply with racist laws and rules. Griffin, again depressed and weary of life as a black man, briefly stops taking his medication and lightens his skin back to his normal color. He begins alternating back and forth between races, visiting a place first as a black man and then as a white man. He notices immediately that when he is a white man, whites treat him with respect and blacks treat him with suspicious fear; when he is a black man, blacks treat him with generosity and warmth, while whites treat him with hostility and contempt. Griffin concludes that the races do not understand one another at all, and that a tolerant dialogue is needed to bridge the terrible gap separating them.
In Atlanta, Griffin conducts a long series of interviews with black leaders before returning to New Orleans to make a photographic record of his time there. He then goes off his medication entirely, permanently returning his skin color to white. He returns home to his family and writes his article, which is published in March 1960. After the article appears, Griffin is called on to do interviews with prominent television shows and newsmagazines. The story of his amazing experience quickly spreads around the world, and he receives a flood of congratulatory mail. In Mansfield, however, the prevalent attitude is that of racism, and Griffin and his family become the subject of hateful reprisals. An effigy of Griffin, painted half white and half black, is burned on Main Street; a cross is burned in a Negro schoolyard; threats are made against Griffin, including one to castrate him. By August, things are so bad that he has decided to move his family to Mexico. Before he goes, he has a talk with a little black boy, to whom he explains that racism is a result of social conditioning, not any inherent quality within blacks or whites. He issues a plea for tolerance and understanding between the races, fearing that, if the current conflict is sustained, it will explode in an outbreak of terrible violence.