Identifying social determinants of tobacco and alcohol use during pregnancy is critical to improving health outcomes for the next generation. This is especially important on a rural Tribal Nation where influences such as isolation, cultural barriers, and historical trauma have made it uniquely challenging to prevent substance use during pregnancy. The purpose of this study is to identify population-specific factors that are protective against smoking and drinking during pregnancy. We used data from 421 pregnancies collected as a part of the Safe Passages study from a rural Tribal Nation in the central United States. Pregnant women were classified as women who did not smoke (n = 84), women who quit during pregnancy (n = 23), women who smoked during pregnancy (n = 314), and women who both smoked and drank alcohol during pregnancy (n = 149). Demographic data revealed that 28.8% of the mothers were currently employed, and 91.8% of mothers reported a household income of less than $3,000 per year. Substance use rates were higher than national averages: 74.6% smoked during pregnancy and 35.4% of the women both smoked and drank alcohol during pregnancy. Five factors were identified as being protective against substance use during pregnancy: 1) living with someone (81% less likely to smoke and 92% less likely to smoke and drink), 2) having at least 12 years of education (128% less likely to smoke, and 126% less likely to smoke and drink), 3) having over 12 years of education (235% less likely to smoke, and 206% less likely to smoke and drink), 4) being employed (158% less likely to smoke, and 111% less likely to smoke and drink), and 5) not being depressed (214% less likely to smoke, and 229% less likely to smoke and drink). These social determinants should be considered for intervention research to decrease rates of substance use during pregnancy.