The aim of this systematic review was to investigate the effect of exercise-based programmes in the prevention of non-contact musculoskeletal injuries among football players in comparison to a control group. Systematic review and meta-analysis of randomised controlled trials. MEDLINE, EMBASE, CENTRAL, CINAHL, PEDro and SPORTDiscus databases were searched from the earliest record to January 2021. Studies were eligible if they (1) included football players aged 13 years or older, (2) used exercise-based programmes as intervention, (3) presented the number of non-contact musculoskeletal injuries (ie, defined as any acute sudden onset musculoskeletal injury that occurred without physical contact) and exposure hours for each group, and (4) had a control group (eg, usual training, minimal intervention, education). All types of exercise-based prevention programmes were eligible for inclusion. Risk of bias for each included study and overall quality of evidence for the meta-analysis were assessed. Ten original randomised controlled trials with 13 355 football players and 1 062 711 hours of exposure were selected. Pooled injury risk ratio showed very low-quality evidence that exercise-based prevention programmes reduced the risk of non-contact musculoskeletal injuries by 23% (0.77 (95% CI 0.61 to 0.97)) compared with a control group. Exercise-based prevention programmes may reduce the risk of non-contact musculoskeletal injuries by 23% among football players. Future high-quality trials are still needed to clarify the role of exercise-based programmes in preventing non-contact musculoskeletal injuries among football players. CRD42020173017.