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Background Youth comprise 40% of the world’s unemployed, a status associated with adverse wellbeing and social, health, and economic costs. This systematic review and meta-analysis review synthesises the literature on the effectiveness of interventions targeting young people not in employment, education, or training (NEET). Methods Randomised and quasi-randomised trials with a concurrent or counterfactual control group and baseline equivalence are included. Cochrane collaboration tools are used to assess quality, and a narrative synthesis was undertaken. The primary outcome is employment; secondary outcomes were health, earnings, welfare receipt, and education. Results Eighteen trials are included (9 experimental and 9 quasi-experimental), sample sizes range from 32 to 54,923. Interventions include social skills, vocational, or educational classroom-based training, counselling or one-to-one support, internships, placements, on-the-job or occupational training, financial incentives, case management, and individual support. Meta-analysis of three high-quality trials demonstrates a 4% (CI 0.0–0.7) difference between intervention and control groups on employment. Evidence for other outcomes lacks consistency; however, more intensive programmes increase employment and wages over the longer term. Conclusions There is some evidence that intensive multi-component interventions effectively decrease unemployment amongst NEETs. The quality of current evidence is limited, leaving policy makers under-served when designing and implementing new programmes, and a vulnerable population neglected. Systematic review registration PROSPERO CRD42014007535 Electronic supplementary material The online version of this article (doi:10.1186/s13643-016-0394-2) contains supplementary material, which is available to authorized users.