ABSTRACT Purpose This study assessed the relationship of spirituality, social support, and sense of mastery to life satisfaction and quality of life to identify viable psychosocial coping resources among American Indian (AI) women cancer survivors. Method We conducted a cross-sectional survey of 73 AI women cancer survivors residing in South Dakota. A series of multivariate hierarchical regression analyses was conducted. Results Findings indicated that lower self-rated physical health was consistently associated with lower levels of life satisfaction and quality of life. Spirituality was found to be the most influential predictor for life satisfaction, while social support and sense of mastery were two significant predictors for quality of life. Discussion Our data underscored the importance of spirituality, social support, and sense of mastery to the well-being of AI women cancer survivors and as effective coping strategies to mitigate life stressors. Implications of this evidence for the design of cancer preventions and interventions are discussed.