Background: Grandmothers living with grandchildren face stressors that may increase depressive symptoms, but cognitive-behavioral strategies, such as resourcefulness, may reduce the effects of stressors on mental health. Purpose: This analysis examined the contemporaneous and longitudinal relationships among intra-family strain, resourcefulness, and depressive symptoms in 240 grandmothers, classified by caregiving status to grandchildren. Methods: Grandmothers raising grandchildren, grandmothers living in multigenerational homes, and non-caregivers to grandchildren reported on intra-family strain, resourcefulness, and depressive symptoms using mailed questionnaires at three time points over 5 years. Structural equation modeling was used to evaluate the mediating effects of resourcefulness and the relationships between variables. Discussion: Grandmother caregiver status had significant effects on depressive symptoms and intra-family strain but not on resourcefulness. At all waves, higher resourcefulness was associated with fewer depressive symptoms, which reduced appraisals of intra-family strain. Conclusions: Interventions focused on strengthening resourcefulness could reduce depressive symptoms over time.