Melatonin has been proved to have positive effects on cellular damage and metabolic regulation. The aim of the study was to determine the effect of melatonin supplementation during an intensive training period on physical performance decline, oxidative stress and cellular damage state. The investigation was conducted on 20 soccer players who participated in an exhaustive six-day training schedule associated with daily 5 mg oral melatonin or placebo ingestion. Resting blood samples and physical performance were measured before and after the training period. The mixed 2-way ANOVA (group x training camp) showed that compared to placebo, melatonin intake prevented an increase in advanced oxidation protein products (p>0.05) and increased the antioxidant enzyme activity (i.e., superoxide dismutase; p<0.001). In addition, melatonin prevented an increase of biomarkers of renal function (e.g., creatinine; p>0.05) and biomarkers of muscle (e.g., creatine kinase; p>0.05) and liver (e.g., gamma-glutamyltransferase; p>0.05) damage. Furthermore, melatonin alleviated the deterioration in physical performance (countermovement jump, five-jump test and 20-m sprint; p>0.05). In conclusion, the obtained data showed increased oxidative stress and renal, muscle and liver damage in professional soccer players during an exhaustive training schedule. Melatonin intake during the training period exerts beneficial effects on physical performance and protects tissues against the deleterious effects of reactive oxygen species and cellular damage.