The present study examined the mediating role of depression symptoms in the relation of college stress and minority status stress to cumulative grade point average (GPA) and persistence intentions among Hispanic women (n = 426) enrolled in a 4-year major research public institution. Results of path analyses indicated a strong model-data fit for the proposed model. When controlling for each other, both typical college stress and minority status stress positively predicted depression and, in turn, depression negatively predicted college persistence intentions. Tests of indirect effects revealed that depression mediated the relation of college stress and minority status stress to persistence. No mediation effects were present in the relation of the stress variables to cumulative GPA. Findings suggest that depression symptoms is one of the pathways through which college stress and minority status stress may result in lower levels of persistence intentions and, possibly, dropout behavior among Hispanic college women in 4-year institutions.