BACKGROUND: Interventions aimed at reducing risky sexual behavior are considered an important strategy for averting Human Immunodeficiency Virus (HIV) infection among youth (15-24 years) who continue to be at risk of the disease. Enhancing intervention success requires a comprehensive understanding of the barriers and facilitators to interventions targeting youth. However, there is lack of a systematic review of both quantitative and qualitative studies to comprehensively identify and synthesize barriers and facilitators to HIV prevention interventions for reducing risky sexual behavior among youth worldwide. This review aimed to identify and synthesize barriers and facilitators to HIV prevention interventions for reducing risky sexual behavior among youth globally based on original peer-reviewed studies published in the last decade. METHODS: The Joanna Briggs Institute approach for mixed methods systematic reviews and Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used to guide this review. Nine electronic databases, Joint United Nations Programme on HIV/AIDS and World Health Organization websites, and reference lists of included studies and systematic reviews on barriers and facilitators to HIV prevention interventions for reducing risky sexual behavior among youth were searched for eligible articles. Studies that met the inclusion criteria underwent quality appraisal and data extraction. Findings were analyzed using thematic synthesis and underpinned by Nilsen, 2015's Determinant Framework. RESULTS: Overall 13 studies comprising of eight qualitative studies, four quantitative studies and one mixed methods study were included in the review. Several barriers and facilitators across the five Determinant Framework domains were identified. Most of the barriers fell under the characteristics of the context domain (e.g., gender-biased norms). The next important group of barriers emerged within the characteristics of the end users domain (e.g., fear of relationship breakdown). In terms of facilitators, the majority fell under the characteristics of the strategy of facilitating implementation domain (e.g., implementation of intervention with fidelity) and characteristics of the end users domain (e.g., fear of pregnancy or sexually transmitted infections). The next common set of facilitators appeared within the characteristics of the context domain (e.g., family support). CONCLUSION: This review identified several multi-level barriers and facilitators to HIV prevention interventions for reducing risky sexual behavior among youth. Multi-level and combination approaches are needed to address these factors and enhance intervention success.