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Young people aged 15−24 years comprise one-fourth of incident HIV infections in Southeast Asia. Given the high prevalence and impact of mental health issues among young people, we explored intersections of HIV and mental health, with a focus on adolescent and young key populations (AYKP) in Indonesia, the Philippines, Thailand, and Vietnam. Sixteen focus group discussions (4/country) with young people (n = 132; 16−24 years) and 41 key informant interviews with multisectoral HIV experts explored young people's lived experiences and unmet needs, existing programmes, and strategic directions for local and regional HIV responses. Cross-cutting challenges emerged in healthcare, family, school, and peer domains amid fragmented and under-resourced HIV and mental health services in socio-politically fraught environments. We identified strategic opportunities and initiatives in development and integration of youth-friendly HIV and mental health services; programmes to promote parent–adolescent communication about sex and HIV; and teacher training and resources to advance HIV and mental health awareness, serve as first-responders, and provide community referrals. Youth-led peer education programmes and LGBT-networks were central to the HIV response—promoting HIV prevention, sexual health, and mental health awareness for young people, and resilience and socioeconomic empowerment of peer educators themselves—thereby transforming sociocultural and political contexts of vulnerability. [ABSTRACT FROM AUTHOR]