Background Libya is facing a rapidly growing epidemic of illicit drug use and HIV. This situation is fueled by a complex array of factors, mainly the consequences of the political and military turmoil of the Arab Spring. Although it is extensively documented in other settings that young people are one of the most vulnerable groups to both HIV and illicit drug use, no study has explored this issue among young people in Libya. The current study addresses this research gap. Methods This study is a qualitative study using in-depth interviews guided by a semi-structured questionnaire. We used a maximum variation, purposive sampling strategy to recruit male and female participants, aged 14–18 years, from schools, prisons, and community-based informal re-education and rehabilitation centers in Tripoli, Libya. Results In total, 31 participants were recruited: 6 females and 25 males. Sixteen participants were prisoners and residents of community-based informal re-education and rehabilitation centers, and 15 were recruited in schools. Risk factors for drug use included peer influence, the increased availability and affordability of drugs, disruption of social life and healthy recreational activities, and the distress and casualties of the war. Protective factors were religious beliefs and practices, good parent-child connectedness, and high self-esteem and future aspiration. Risk factors for HIV were insufficient knowledge related to HIV transmission and unsafe injection practices, such as sharing needles and syringes. Conclusion We found individual, interpersonal, family, and structural-level factors that interplayed to shape the vulnerability of young people to drug use and HIV infection in Tripoli, Libya. Structural factors, including the increased availability and affordability of drugs, provided the frame within which other factors, such as peer influence, insufficient knowledge of substance use, and HIV, operated to increase the vulnerability of young people to drugs and HIV, while religious beliefs and parent-child connectedness acted as protective factors. Multisectoral efforts and studies to quantitatively evaluate the magnitude and distribution of these problems are urgently needed.