The association of psychosocial factors (psychological distress, coping skills, family support, trauma exposure, and spirituality) with initial weight and weight loss among American Indians and Alaska Natives (AI/ANs) in a diabetes prevention translational project was investigated. Participants (n = 3,135) were confirmed as prediabetic and subsequently enrolled in the Special Diabetes Program for Indians Diabetes Prevention (SDPI-DP) demonstration project implemented at 36 Indian health care programs. Measures were obtained at baseline and after completing a 16-session educational curriculum focusing on weight loss through behavioral changes. At baseline, psychological distress and negative family support were linked to greater weight, whereas cultural spirituality was correlated with lower weight. Furthermore, psychological distress and negative family support predicted less weight loss, and positive family support predicted greater weight loss, over the course of the intervention. These bivariate relationships between psychosocial factors and weight remained statistically significant within a multivariate model, after controlling for sociodemographic characteristics. Conversely, coping skills and trauma exposure were not significantly associated with baseline weight or change in weight. These findings demonstrate the influence of psychosocial factors on weight loss in AI/AN communities and have substantial implications for incorporating adjunctive intervention components.