Informed by the social control theoretical perspective, this study intends to identify the factors more likely to differentiate American Indian (AI) adolescents who never used illicit drugs (abstainers) and those who used drugs in the past but did not report recent drug usage (desisters) from their peers who reported lifetime and recent drug usage (persisters). This secondary analysis is based on data from a multi-site study conducted between 2009 and 2013. It is based on a gender-balanced sample (N = 3,380) of AI adolescents (50.50% male; Mean age = 14.75; SD = 1.69) representing the major AI languages and cultural groups in the U.S. Half of the AI adolescents reported lifetime drug use (50.40%), 37.50% never used drugs, and 12.10% stopped using drugs. When controlling for the variables included in the analysis, AI boys were significantly more likely than AI girls to desist from drug use. Both boys and girls who never used drugs tended to be younger, were less likely to have delinquent friends and a lower level of self-control, had stronger bonds to school, but lower levels of family attachment, and reported increased parental supervision. Compared to drug users, desisters associated significantly less with delinquent peers. While school attachment, self-control, and parental monitoring did not differentiate female desisters from female drug users, adolescent boys who desisted from drug use were more likely to report higher levels of school attachment and parental monitoring and their level of self-control was less likely to be low.