Indigenous peoples have not only experienced a devastating rate of historical loss of lives, they are more likely to experience mortality disparities. The purpose of this article is to examine Indigenous women's lived experiences of grief and loss in two Southeastern tribes and the relationship between depressive symptoms and recent loss of a loved one. Our exploratory sequential mixed-methods research was informed by the Indigenous based Framework of Historical Oppression, Resilience, and Transcendence (FHORT). We summarized key qualitative themes from ethnographic data from 287 female participants across the two tribes, collected through focus groups, family interviews, and individual interviews. We then quantitatively examined how these themes predicted depressive outcomes among 127 respondents. Specifically, we examined associations between depressive symptoms and components of historical oppression-historical loss, loss of lives, and the presence of PTSD symptoms-along with resilience and transcendence.