In urban northern Nigeria, traditional family systems are fracturing under economic strain and rising divorce rates, creating a protective vacuum that drives adolescents into substance abuse. Utilizing a convergent parallel mixed-methods design, this empirical study investigated how modern family transitions shape gender-differentiated youth vulnerability and substance abuse patterns across six high-burden Local Government Areas (LGAs) in Kano State: Kano Municipal, Dala, Tarauni, Gwale, Nasarawa, and Kumbotso. Data were gathered from a proportionately balanced sample of 450 adolescents aged 15–21. Quantitative surveys established that family structural disruptions significantly correlate with early substance initiation. Simultaneously, thematic analysis of 24 gender-segregated focus group discussions unmasked starkly divergent, gendered behavioral pathways. Males from fractured homes heavily gravitated toward public, peer-driven consumption of volatile inhalants and solvents, triggered by a structural lack of positive male mentorship. Conversely, females exhibited a highly concealed but widespread prevalence of prescription medication abuse (tramadol and codeine-based syrups) within domestic spaces, uniquely driven by internalized emotional trauma and a collapse of paternal oversight. These findings prove that youth substance dependency is deeply rooted in domestic instability rather than mere criminality. This paper argues for a paradigm shift in the Nigerian health system, advocating for the integration of decentralized, gender-tailored mental health toolkits and family-counseling frameworks directly into primary healthcare centers to achieve sustainable, last-mile intervention.