Anterior cruciate ligament (ACL) is one of the most concerning injuries for football players. The aim of this review is to investigate the effects of exercise-based interventions targeting at reducing ACL injury rate or mitigating risk factors of ACL injury in adult football players. Following PRISMA guidelines, a systematic search was conducted in CINAHL, Cochrane Library, PubMed, Scopus, SPORTDiscus and Web of Science. Studies assessing the effect of exercise-based interventions in ACL injury incidence or modifiable risk factors in adult football players were included. 29 studies evaluating 4502 male and 1589 female players were included (15 RCT, 8 NRCT, 6 single-arm): 14 included warm-up, 7 resistance training, 4 mixed training, 3 balance, 1 core stability and 1 technique modification interventions. 6 out of 29 studies investigated the effect of interventions on ACL injury incidence, while the remaining 23 investigated their effect on risk factors. Only 21% and 13% studies evaluating risk of injury variables reported reliability measures and/or smallest worthwhile change data. Warm-up, core stability, balance and technique modification appear effective and feasible interventions to be included in football teams. However, the use of more ecologically valid tests and individually tailored interventions targeting specific ACL injury mechanisms are required.