Few studies have specifically focused on meaning in life in African Americans and many important questions remain, including whether effects of meaning in life are direct or moderated by levels of stress. In a national sample of 909 African Americans, we tested meaning in life as a prospective predictor of changes in depressive symptoms and positive affect over a 2.5-year period. Controlling for demographics and hassles, meaning in life predicted decreased depressive symptoms and increased positive affect across the span of 2.5 years. Moderation effects were not found for hassles, age, or income. Gender moderated the effect of meaning on positive affect such that effects were stronger for women than for men. These results suggest that, for African Americans, meaning in life appears to robustly protect against future depressive symptoms and promote positive affect over time unaffected by amount of stress experienced or most demographic factors.