African American men have the lowest life expectancy of any ethnic gender group in the USA. Furthermore, these men endorse having a lower health-related quality of life (HRQoL) than any other group. There have been recent calls from national organizations to improve HRQoL—a multidimensional indicator of health strongly associated with mortality and morbidity. Following these calls, there have been widespread efforts implemented to improve HRQoL among the US population, though no known effort has been implemented that is tailored to the unique experiences of African American men. Health promotion efforts that are not tailored to the unique preferences and experiences of these men are likely to produce limited results. Formative research conducted among African American men is needed in order to design and implement an effective HRQoL-promoting intervention for African American men. The present study constitutes such formative research and was conducted with a sample of 211 African American men. Hierarchical regressions were performed to understand the role of literature-derived predictors of HRQoL among these men. Results found that depression, stress, and physical activity were found to be significant predictors of HRQoL among these men. This is the first known study to examine predictors of HRQoL among African American men—a group that disproportionately experiences health disparities and low HRQoL, though for who few successful health promotions exist. The findings from this study have implications for those seeking to design and implement HRQoL-promoting interventions among African American men.