The protagonist, Neil Kingsblood, a white middle-class man, discovers while researching his family background that he is directly descended from an African adventurer on the American frontier.

Earlier on in his career, Lewis had reconnected with a childhood friend, Edward Francis Murphy, a priest who was a member of the Josephites (a Catholic society that specifically works with African Americans).

[2] Additionally, Lewis met Walter Francis White, president of the NAACP and a man of majority European ancestry, and many of his professional circles.

Kenneth L. Patton of the First Unitarian Church in Madison, Wisconsin, having read the novel, formally "renounced" the white race and declared himself "colored," saying he was one sixty-fourth Native American.

"[4] Shortly after the publication of Kingsblood Royal, a group of white supremacists sent a letter to J. Edgar Hoover encouraging the FBI to seize all copies of the book and declare Lewis' novel an act of sedition.