The current study examined associations over an 18-month period between maternal work stressors, negative work-family spillover, and depressive symptoms in a sample of 414 employed mothers with young children living in six predominantly nonmetropolitan counties in the Eastern United States. Results from a one-group mediation model revealed that a less flexible work environment and greater work pressure predicted higher levels of depressive symptoms, and further, that these associations were mediated by perceptions of negative work-family spillover. Additionally, results from a two-group mediation model suggested that work pressure predicted greater perceptions of spillover only for mothers employed full-time. Findings suggest the need for policies that reduce levels of work stress and help mothers manage their work and family responsibilities.