Objective: Recent research has indicated that historical loss may play an important role in the experience of depression symptoms in American Indian/Alaska Native people. Increased frequency of historical loss thinking has been related to symptoms of depression and other pervasive psychological outcomes (i.e., substance abuse) in American Indian and Canadian First Nations communities. The current study investigated how aspects of ethnic minority experience relate to the incidence of historical loss thinking and symptoms of depression in American Indian adults. Method: Data are presented from 123 self-identified American Indian college students (ages 18–25, 67.50% female) who participated in the study in return for course credit and/or entrance into a raffle for gift cards. Participants completed the Adolescent Historical Loss Scale (AHLS), Scale of Ethnic Experiences (SEE), and the Center for Epidemiologic Studies–Depression Scale (CES-D). Indirect effects of ethnic experience on symptoms of depression through historical loss thinking were calculated with nonparametric bootstrapping procedures. Results and Conclusions: Results indicated that a strong ethnic identification, desire to predominantly socialize with other American Indians, and perceptions of discrimination were associated with increased historical loss thinking. Feelings of comfort and assimilation with the mainstream American culture were negatively related to historical loss thinking. Only perception of discrimination was directly related to symptoms of depression; however, ethnic identification and the preference to predominantly socialize with other American Indians were both indirectly related to elevated depressive symptoms through increased historical loss thinking. The clinical implications for these results are discussed.