BACKGROUND: Playing football is associated with a high risk of injury. Injury prevention is a priority as injuries not only negatively impact health but also potentially performance. Various multi-component exercise-based injury prevention programs for football players have been examined in studies. OBJECTIVE: We aimed to investigate the efficacy of multi-component exercise-based injury prevention programs among footballers of all age groups in comparison to a control group. METHODS: We conducted a systematic review and meta-analysis of randomized and cluster-randomized controlled trials. CINAHL, Cochrane, PubMed, Scopus, and Web of Science databases were searched from inception to June 2022. The following inclusion criteria were used for studies to determine their eligibility: they (1) include football (soccer) players; (2) investigate the preventive effect of multi-component exercise-based injury prevention programs in football; (3) contain original data from a randomized or cluster-randomized trial; and (4) investigate football injuries as the outcome. The risk of bias and quality of evidence were assessed using the Cochrane Risk of Bias Tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. The outcome measures were the risk ratio (RR) between the intervention and the control group for the overall number of injuries and body region-specific, contact, and non-contact injuries sustained during the study period in training and match play. RESULTS: Fifteen randomized and cluster-randomized controlled trials with 22,177 players, 5080 injuries, and 1,587,327 exposure hours fulfilled the inclusion criteria and reported the required outcome measures. The point estimate (RR) for the overall number of injuries was 0.71 (95% confidence interval [CI] 0.59-0.85; 95% prediction interval [PI] 0.38-1.32) with very low-quality evidence. The point estimate (RR) for lower limb injuries was 0.82 (95% CI 0.71-0.94; 95% PI 0.58-1.15) with moderate-quality evidence; for hip/groin injuries, the RR was 0.56 (95% CI 0.30-1.05; 95% PI 0.00-102.92) with low-quality evidence; for knee injuries, the RR was 0.69 (95% CI 0.52-0.90; 95% PI 0.31-1.50) with low-quality evidence; for ankle injuries, the RR was 0.73 (95% CI 0.55-0.96; 95% PI 0.36-1.46) with moderate-quality evidence; and for hamstring injuries, the RR was 0.83 (95% CI 0.50-1.37) with low-quality evidence. The point estimate (RR) for contact injuries was 0.70 (95% CI 0.56-0.88; 95% PI 0.40-1.24) with moderate-quality evidence, while for non-contact injuries, the RR was 0.78 (95% CI 0.55-1.10; 95% PI 0.25-2.47) with low-quality evidence. CONCLUSIONS: This systematic review and meta-analysis indicated that the treatment effect associated with the use of multi-component exercise-based injury prevention programs in football is uncertain and inconclusive. In addition, the majority of the results are based on low-quality evidence. Therefore, future high-quality trials are needed to provide more reliable evidence. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42020221772.