Background <p>Adolescent girls and young women (AGYW) aged 15 to 24 years continue to bear a disproportionate burden of HIV infections in sub–Saharan Africa. Although substantial research has examined behavioral risk factors, evidence on how individual, interpersonal, and structural determinants interact to shape HIV vulnerability remains fragmented. A clearer synthesis of these intersecting determinants is essential for informing integrated HIV prevention strategies and guiding the implementation of emerging biomedical interventions such as long-acting pre-exposure prophylaxis.</p> Methods <p>A systematic review was conducted in accordance with PRISMA 2020 guidelines. Five electronic databases, namely PubMed, Scopus, Web of Science, Embase, and CINAHL, were searched for peer reviewed studies examining determinants of HIV vulnerability among AGYW in sub–Saharan Africa. Eligible studies included quantitative, qualitative, and mixed methods designs reporting empirical evidence on factors associated with HIV vulnerability. Findings were synthesized using a social ecological framework. Meta analysis was conducted for determinants with comparable quantitative effect estimates.</p> Results <p>A total of 49 studies conducted across 18 countries were included. Of these, 12 studies contributed to quantitative synthesis, while the remaining studies contributed to narrative synthesis. Meta analysis showed that age discordant partnerships, transactional sex, and intimate partner violence were significantly associated with increased HIV vulnerability among AGYW, with pooled estimates indicating consistent elevated risk across studies. Across studies not included in meta-analysis, poverty, food insecurity, school dropout, and migration were consistently identified as structural drivers of vulnerability. At the individual level, low perceived susceptibility to HIV and inconsistent condom use were frequently reported risk behaviors, often influenced by gender power imbalance, partner control, and economic dependence.</p> Conclusion <p>HIV vulnerability among AGYW in sub–Saharan Africa is driven by interacting behavioral, relational, and structural determinants. These findings highlight the need for integrated HIV prevention strategies that combine behavioral interventions with structural responses addressing poverty, gender inequality, and access to youth friendly health services. At the policy level, national HIV response frameworks should strengthen cross sector collaboration across health, education, and social protection systems to address the broader conditions that sustain vulnerability. Future research should prioritize longitudinal and implementation studies to better understand causal pathways and evaluate multilevel interventions across diverse contexts.</p>