There is limited evidence demonstrating the benefits of physical activity with regard to mortality risk or the harms associated with sedentary behavior in black adults, so we examined the relationships between these health behaviors and cause-specific mortality in a prospective study that had a large proportion of black adults. Participants (40-79 years of age) enrolled in the Southern Community Cohort Study between 2002 and 2009 (n = 63,308) were prospectively followed over 6.4 years, and 3,613 and 1,394 deaths occurred in blacks and whites, respectively. Black adults who reported the highest overall physical activity level (≥32.3 metabolic equivalent-hours/day vs. <9.7 metabolic equivalent-hours/day) had lower risks of death from all causes (hazard ratio (HR) = 0.76. 95% confidence interval (CI): 0.69, 0.85), cardiovascular disease (HR = 0.81, 95% CI: 0.67, 0.98), and cancer (HR = 0.76, 95% CI: 0.62, 0.94). In whites, a higher physical activity level was associated with a lower risk of death from all causes (HR = 0.76, 95% CI: 0.64, 0.90) and cardiovascular disease (HR = 0.69, 95% CI: 0.49, 0.99) but not cancer (HR = 0.95, 95% CI: 0.67, 1.34). Spending more time being sedentary (>12 hours/day vs. <5.76 hours/day) was associated with a 20%-25% increased risk of all-cause mortality in blacks and whites. Blacks who reported the most time spent being sedentary (≥10.5 hours/day) and lowest level of physical activity (<12.6 metabolic equivalent-hours/day) had a greater risk of death (HR = 1.47, 95% CI: 1.25, 1.71). Our study provides evidence that suggests that health promotion efforts to increase physical activity level and decrease sedentary time could help reduce mortality risk in black adults.