Background Alcohol use is a leading risk factor for death and disability worldwide. Aims We conducted a systematic review on the cost-effectiveness evidence for interventions to prevent alcohol use across the lifespan. Method Electronic databases (EMBASE, Medline, PsycINFO, CINAHL and EconLit) were searched for full economic evaluations and return-on-investment studies of alcohol prevention interventions published up to May 2021. The methods and results of included studies were evaluated with narrative synthesis, and study quality was assessed by the Drummond ten-point checklist. Results A total of 69 studies met the inclusion criteria for a full economic evaluation or return-on-investment study. Most studies targeted adults or a combination of age groups, seven studies comprised children/adolescents and one involved older adults. Half of the studies found that alcohol prevention interventions are cost-saving (i.e. more effective and less costly than the comparator). This was especially true for universal prevention interventions designed to restrict exposure to alcohol through taxation or advertising bans; and selective/indicated prevention interventions, which involve screening with or without brief intervention for at-risk adults. School-based interventions combined with parent/carer interventions were cost-effective in preventing alcohol use among those aged under 18 years. No interventions were cost-effective for preventing alcohol use in older adults. Conclusions Alcohol prevention interventions show promising evidence of cost-effectiveness. Further economic analyses are needed to facilitate policy-making in low- and middle-income countries, and among child, adolescent and older adult populations.