Physical inactivity and sedentary behavior are recognized as independent risk factors for many diseases. However, studies investigating their associations with total and cause-specific mortality in low-income and Black populations are limited, particularly among older adults. A prospective cohort study was conducted among 8,337 predominantly low-income and Black Americans aged ≥65 years residing in the southern United States. Participants reported their daily sitting time and leisure-time physical activity (LTPA) at baseline (2002-2009), and mortality data were collected through 2019. Analysis was conducted from September 2022 to October 2023. During a median follow-up of 12.25 years, nearly 50% (n=4,111) were deceased. A prolonged sitting time (>10 hours/day versus <4 hours/day) was associated with elevated all-cause mortality (hazard ratios [HR], 1.15; 95% confidence intervals [CI], 1.04-1.27) after adjusting for LTPA and other potential confounders. LTPA was associated with a reduced risk of all-cause mortality, with an adjusted HR of 0.75 (95% CI 0.64, 0.88) associated with 150-300 minutes per week of moderate-intensity physical activity. Individuals who were physically inactive and had a sitting time of >10 hours/day had the highest mortality risk (HR, 1.48; 95% CI, 1.23-1.78), compared with those who were physically active and had low sitting time. These associations were more pronounced for mortality due to cardiovascular diseases. High sitting time is an independent risk factor for all-cause and cardiovascular disease mortality, and LTPA could partially attenuate the adverse association of prolonged sitting time with mortality.