Taking a comprehensive biopsychosocial approach and using a two-wave longitudinal design, this study examines the relation between brain development and the social environment in Mexican American youth’s (N = 41.56 percent female) academic achievement and substance use. We find that both Mexican American youth’s structural brain development and social environment uniquely contribute to their adjustment. Specially, smaller hippocampal volume and parental cultural socialization each uniquely predict better academic achievement. Moreover, smaller nucleus accumbens volume and less affiliation with deviant peers each uniquely predict less substance use. These findings underscore the independent contributions of biological and psychosocial factors in youth’s adjustment. The study provides a new biopsychosocial perspective on Mexican American youth’s well-being.