Using national longitudinal survey data from the Fragile Families & Child Wellbeing Study (FFCWS), this study builds on existing knowledge about housing insecurity, female caregivers, and well-being. The study analyzed the relationship between housing cost burdens (HCB) and depression among a sample (N = 399) of predominantly (67.6%) Black non-Hispanic mothers and other female primary caregivers. A generalized estimating equation (GEE) model yielded results that indicate housing cost burden among mothers and other female primary caregivers has a statistically significant association with meeting symptoms of depression and liberal criteria for depression as measured by the CIDI-SF survey instrument. This study contributes to the knowledge base of health outcomes related to housing cost burden by providing a unique analysis of the association of depression and housing cost burden at an unprecedented scale by using data from several consecutive waves of survey responses of a large, multi-city, longitudinal study. The findings hold implications that may inform future policy and research concerning the affordable housing crisis, which disproportionately affects mothers and other female heads of household. Considering the prevalence of housing cost burden in the USA and the disproportionate indications of depression found among housing burdened mothers/female caregivers, the findings of this study may hold implications for housing and health policies that address U.S. communities as diverse as the wide range of communities from which the FFCWS respondents were drawn.