Although cognitive behavioral interventions (CBIs) have demonstrated effectiveness for reducing depressive symptoms in the general population, the mechanism for reducing antepartum depressive symptoms (APDS) in rural low-income and minority women is unknown. This study tested the hypothesis that reducing stress and negative thinking, enhancing self-esteem, and increasing social-support will mediate the effect of a CBI on reducing APDS in rural low-income and minority women. Our findings show that CBI may work through reducing stress and negative thinking and enhancing self-esteem, but not social support. The findings also suggest that mental health care providers should emphasize these activities to reduce antepartum depressive symptoms.