William Edward Burghardt Du Bois is considered one of the most prolific and brilliant scholars of our time. While his contributions to civil rights, sociology, history, African American studies, and urban studies are universally recognized, his legacy in the public health and epidemiology discourses is not as widely acknowledged by contemporary health researchers. His seminal work The Philadelphia Negro: A Social Study (1899) and his report “The Health and Physique of the Negro American” (1906) may be considered early harbingers in general of public health—and more specifically, social epidemiology—research. During the late nineteenth and early twentieth centuries, Black and White differences in mortality and morbidity were largely attributed to notions of biological racial inferiority. Efforts by Du Bois to challenge these predominant notions resulted in the systematic empirical investigation of social factors contributing to Black health risk and health disparities. More than one hundred years after Du Bois's pioneering scholarship, racial/ethnic and social disparities remain a central challenge for public health and medical professionals. Given the persistence of health disparities and the increasing focus on neighborhood social and physical environments as fundamental factors contributing to health inequalities, this paper seeks to historically situate Du Bois's scholarship, describe the methodological and conceptual significance of his seminal studies, and articulate the importance of incorporating Du Bois's legacy to advance the next generation of racial/ethnic health inequality research.