African Americans (AAs) are disproportionately affected by cerebrovascular pathology and more likely to suffer from premature cognitive decline. Depression is a risk factor for poorer cognitive functioning, and research is needed to identify factors that serve to mitigate its negative effects. Studies have demonstrated positive influences of spirituality within the AA community. Determining whether spirituality attenuates the effects of depressive symptoms on cognitive functioning and the pathophysiological mechanisms that explain these relationships in AAs is paramount. This study examines the influence of daily spiritual experiences on the relationship between depressive symptoms and cognitive functioning, and how inflammatory markers may partially explain these associations. A sample of 212 (mean age= 45.6) participants completed the Daily Spiritual Experience Scale (DSES), Beck Depression Inventory-II (BDI-II), Trail Making Test A and B (TMT) and Stroop Color and Word Test (Stroop). Blood samples were collected to measure inflammatory mediators (IL-6, IL-1a, TNF-a). Linear regression analyses were used to evaluate associations. Higher BDI-II scores were associated with poorer psychomotor speed and visual scanning, measured by TMT A (B=1.49, P=.01). IL-6 explained a significant amount of variance in this relationship (B=.24, CI 95% [.00, .64]). IL-6 also significantly mediated the relationship between depressive symptoms and psychomotor speed and mental flexibility, measured by TMT B performance (B=.03, CI 95% [.003, .095]). Frequent spiritual experiences among AAs may ameliorate the negative influence of depressive symptoms on cognitive functioning.Ethn Dis. 2019;29(2):267-276; doi:10.18865/ed.29.2.267