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Introduction: Social protection programmes are considered HIV‐sensitive when addressing risk, vulnerability or impact of HIV infection. Socio‐economic interventions, like livelihood and employability programmes, address HIV vulnerabilities like poverty and gender inequality. We explored the HIV‐sensitivity of socio‐economic interventions for unemployed and out‐of‐school young women aged 15 to 30 years, in East and Southern Africa, a key population for HIV infection. Methods: We conducted a systematic review using a narrative synthesis method and the Mixed Methods Appraisal Tool for quality appraisal. Interventions of interest were work skills training, microfinance, and employment support. Outcomes of interest were socio‐economic outcomes (income, assets, savings, skills, (self‐) employment) and HIV‐related outcomes (behavioural and biological). We searched published and grey literature (January 2005 to November 2019; English/French) in MEDLINE, Scopus, Web of Science and websites of relevant international organizations. Results: We screened 3870 titles and abstracts and 188 full‐text papers to retain 18 papers, representing 12 projects. Projects offered different combinations of HIV‐sensitive social protection programmes, complemented with mentors, safe space and training (HIV, reproductive health and gender training). All 12 projects offered work skills training to improve life and business skills. Six offered formal (n = 2) or informal (n = 5) livelihood training. Eleven projects offered microfinance, including microgrants (n = 7), microcredit (n = 6) and savings (n = 4). One project offered employment support in the form of apprenticeships. In general, microgrants, savings, business and life skills contributed improved socio‐economic and HIV‐related outcomes. Most livelihood training contributed positive socio‐economic outcomes, but only two projects showed improved HIV‐related outcomes. Microcredit contributed little to either outcome. Programmes were effective when (i) sensitive to beneficiaries' age, needs, interests and economic vulnerability; (ii) adapted to local implementation contexts; and (iii) included life skills. Programme delivery through mentorship and safe space increased social capital and may be critical to improve the HIV‐sensitivity of socio‐economic programmes. Conclusions: A wide variety of livelihood and employability programmes were leveraged to achieve improved socio‐economic and HIV‐related outcomes among unemployed and out‐of‐school young women. To be HIV‐sensitive, programmes should be designed around their interests, needs and vulnerability, adapted to local implementation contexts, and include life skills. Employment support received little attention in this literature. [ABSTRACT FROM AUTHOR]