This study examined the associations among religion, social support, and life satisfaction with 233 older American Indians in the Northern Plains region. Hierarchical regression indicated that those with higher religiousness and greater social support were found to have greater life satisfaction. Findings suggest that religion and social support provide promising pathways to build upon existing strengths to ameliorate mental health disparities. Health professionals must be sensitive to the complexities of religion and social support, and consider ways to incorporate cultural practices into health education and interventions to promote the quality of life for older American Indians.