Abstract Background and Objectives Identifying potential intervention strategies to reduce cognitive decline, particularly among older African Americans at high risk for Alzheimer’s dementia, is critical. This study aimed to investigate whether depressive symptoms, purpose in life, and their interrelations are associated with cognitive decline in older African Americans. Research Design and Methods We included older African Americans from the Minority Aging Research Study (n = 748) and Rush Memory and Aging Project (n = 109), without dementia at baseline. We assessed associations of depressive symptoms, purpose in life, and their interrelations, with baseline levels and change in global cognition using linear mixed-effects models. Results At baseline, each unit increment in depressive symptoms was related to worse initial global cognition (mean difference = −0.03 standard unit; p = .003), while higher purpose in life was related to better cognition (mean difference = 0.12; p = .002). Further, participants with ≥1 depressive symptom who had a purpose in life score above the median appeared to have better global cognition (mean difference = 0.10; p = .01), compared to those with depressive symptoms but lower levels of purpose in life. However, we did not find relations of depressive symptoms or purpose in life with rates of cognitive decline over time, likely due to the modest follow-up. Discussion and Implications In older African Americans, we found that lower depressive symptoms and greater purpose in life were independently related to higher initial levels of global cognition, but not cognitive decline. Preliminary findings of higher global cognition in individuals with depressive symptoms but greater purpose in life merit further investigation if purpose may eventually be considered as an intervention.