The United States and Mexico have seen significant increases in the prevalence of substance use among Latinx adolescents in the last 20 years. Research is needed to address rising national rates of substances use to inform the development of policies and intervention programs targeting Latinx youth. Our primary aim was to identify demographic factors associated with substance initiation and use among elementary age Latinx youth. Data for the present study include 52,171 elementary students in 5th and 6th grades, who participated in the National Survey of Drug Use Among Students (ENCODE) in Mexico. Youths reported demographic information, rates of substance use for alcohol, tobacco, marijuana, inhalant, and other substances, or intention for first time substance use. Findings suggest that Latinx youth who were boys, of indigenous heritage, nonreligious, and overage for their grade were especially at risk for reporting lifetime alcohol, tobacco, marijuana, inhalant, and other substance use. Boys and youth with indigenous heritage were more likely to report intentions to try alcohol, tobacco, and other substances for the first time. High subjective economic status was associated with lower risk for reporting lifetime tobacco use and substance use intentions in general. Efforts are needed to disseminate accessible substance use prevention programs during early adolescence to encourage positive developmental trajectories among Latinx youths at an elevated risk for substance initiation and use. Clinical and research implications are discussed.