Reports of deportation can create a state of chronic fear in children living in mixed-status immigrant families over their own or a loved one's potential deportation. One indicator of health disparities among youth is elevated rates of alcohol, tobacco, and other drug use (ATOD). Yet little is known about the effects of fear of deportation (FOD) on ATOD or what might promote resilience. We explore the associations between FOD and ATOD use, how stress mediates this relationship, and whether hope moderates the mediated pathway from FOD to ATOD. Participants were 200 first- and second-generation 7th grade Hispanic youth (49% female) assessed across three waves of data. A moderated mediation model tested the indirect effect of FOD on ATOD through stress and whether hope moderated these associations. FOD was measured by the Family Fear of Deportation Scale. Snyder's Children's Hope Scale measured hope. Stress was measured by a short version of Pediatric Psychological Stress Measure. ATOD was adapted from the Monitoring the Future project. FOD was not directly associated with ATOD use. However, this path was fully mediated by stress. Hope significantly moderated the path from FOD to stress such that a one unit increase in hope completely offset the effects of FOD on stress. Hope did not moderate the path from stress to ATOD use. Interventions that increase awareness of deportation trauma, alleviate stress, and promote hope may help prevent, delay initiation into, and/or decrease ATOD among Hispanic first- and second-generation youth.