We examined the explanatory roles of social determinants of health (SDOH) for First Nations people using a four-domain model of health and wellness based on the Medicine Wheel (i.e., physical, mental, emotional, and spiritual health), including colonial-linked stressors (i.e., historical trauma, childhood adversities, racial discrimination) and cultural resilience factors (i.e., cultural strengths, traditional healing practices, social support). Data were collected in partnership with a First Nation in Ontario, Canada in 2013 through a community survey (n = 194). For each outcome (physical, mental, emotional, and spiritual health), a modified Poisson regression model estimated prevalence ratios for the SDOH, adjusting for age, sex, education, and marital status. Negative associations were found for historical trauma with physical, mental, emotional, and spiritual health; for childhood adversities with mental health; and for racial discrimination with physical, mental, and emotional health. Positive associations were found for cultural strengths with physical, mental, and emotional health and for social support with physical, mental, emotional, and spiritual health. We observed negative associations between use of traditional healing practices and mental and emotional health. Our findings suggest that these SDOH may play important roles in relation to wellness through associations with the domains of health modelled by the Medicine Wheel.