Nonmedical use of prescription drugs (NMUPD) among U.S. adolescents is a burgeoning public health problem. Previous studies have observed differences in rates of NMUPD among ethnic/racial groups. However, less is known on the social and cultural processes and mechanisms, which may influence adolescents’ prescription drug beliefs and practices. We conducted semi-structured interviews with 20 diverse 13- to 17-year-olds in an adolescent psychiatric inpatient unit to elicit in-depth, context-sensitive information about social factors relevant to NMUPD. Data analysis was completed using grounded theory and interpreted with a social ecological approach. Results highlighted the myriad of important contextual influences on adolescent NMUPD. Responses reflected factors within microsystem, exosystem, and macrosystem contexts as well as important intrapersonal factors. Furthermore, adolescents who identified as an ethnic minority also described cultural values (e.g., religion) and culturally based beliefs (e.g., mental health stigma), which influenced their prescription drug beliefs. Narratives revealed the interplay between intrapersonal factors and socialization agents, such as parents, peers, and the media, influencing prescription drug behavior. Our findings present ecologically framed insights as a first step in understanding this health risk behavior among U.S. adolescents. Implications as well as important next steps for future research and interdisciplinary prevention and intervention program development are discussed.