African American women have more symptoms of depressed mood than white women. Adverse neighborhood conditions may contribute to these symptoms. Although reductions in depressive symptoms with physical activity have been demonstrated in white adults, little research has examined the mental health benefits of physical activity in African American women. Further, it is unknown whether physical activity can offset the effects of living in disadvantaged neighborhoods on depressive symptoms. The purpose of this study was to examine the relationships among neighborhood characteristics, adherence to a physical activity intervention, and change over time in depressive symptoms in midlife African American women.