His debut novel, The Intuitionist, explores ideas surrounding technology and perfection, with members of the school of Intuitionism seeking a version of a Utopia that can't be attained. He also explores ideas surrounding race and stereotypes in this work, as African Americans are stilled referred to as "colored" and the African American characters are doubted, mistrusted, and stereotyped, which is one of the major conflicts in the work.

His debut novel, The Intuitionist, explores ideas surrounding technology and perfection, with members of the school of Intuitionism seeking a version of a Utopia that can't be attained. He also explores ideas surrounding race and stereotypes in this work, as African Americans are stilled referred to as "colored" and the African American characters are doubted, mistrusted, and stereotyped, which is one of the major conflicts in the work.

With several other major works regarding slavery, the Underground Railroad, and more modern stories about the teenage life of African Americans in a white majority school, it is clear that the suffering and experiences of African Americans is at the heart of much of his writing. Other themes clearly relate to the place of technology in human lives, what society and civilization should look like, and the concept of humanity's survival and improvement over time.

John Henry Days is a retelling of the folkloric tale of the mighty John Henry, an African American laborer who valiantly challenged the new machinery that was usurping his role at the railroad. Henry died after beating a steam engine in a race to lay the most railroad track. The book explores historical and folkloric traditions in the African American culture and pits man against technology, championing humanity above the technological advancements that purportedly improve society.

He broke with his typical style and wrote a Zombie science-fiction horror novel called Zone One, which addresses the questions at the core of humanity—what makes people human and what defines civilization? The book also explores the idea of human survival and how humans as a species adapt. Whitehead also shows how racial divides and stereotypes break down when survival is on the line, and how a dangerous epidemic has the benefit of uniting everyone towards a common cause.