Little is known about the relationship between religious coping, spirituality, and substance use in developing nations such as El Salvador. Collected in 2011, the sample consists of 290 high-risk and gang-involved adolescents (11-17 years) and young adults (18-25 years) in San Salvador, El Salvador. Structural equation modeling and logistic regression are employed to examine the associations between the Measure of Religious Coping (RCOPE), the Intrinsic Spirituality Scale, and substance use and abuse. Results suggest that spirituality and, to a far lesser degree, religious coping may serve to protect for substance use and abuse among this high-risk population of Salvadoran youth.