Melatonin and DNA Integrity: The Impact of Exogenous Administration in Exercise-Induced Oxidative Stress—A Systematic Review

Background/Objectives: Intense physical exercise leads to oxidative stress, causing cellular and DNA damage in athletes. Melatonin (MLT), a hormone with antioxidant and anti-inflammatory properties, is increasingly used to counteract these effects. However, its specific role in protecting DNA integrity and modulating repair mechanisms post-exercise remains unclear. This systematic review aimed to synthesize clinical evidence on the effects of exogenous MLT supplementation in reducing exercise-induced oxidative stress, reducing DNA damage, and influencing DNA integrity in healthy, physically active individuals. Methods: A comprehensive search was conducted in PubMed and Scopus up to 25 March 2025, for randomized or controlled clinical trials assessing exogenous MLT in healthy, physically active adults, with outcomes related to oxidative stress, DNA damage, or DNA repair. Risk of bias was evaluated using the RoB2 tool. Due to heterogeneity in study designs and outcomes, results were synthesized narratively. Results: Six clinical trials met the inclusion criteria, with MLT administered as a single dose (6–10 mg) or in repeated doses over 6 days to 4 weeks. Across the studies, MLT consistently reduced oxidative stress markers (malondialdehyde, advanced oxidation protein products), muscle damage indicators (creatine kinase, LDH), and inflammation, while increasing antioxidant enzyme activity (SOD, GPx). Only one study directly assessed DNA damage, reporting significantly reduced DNA fragmentation (comet assay) in the MLT group compared to placebo. No studies directly evaluated DNA repair pathways. Conclusions: Exogenous MLT supplementation appears effective in attenuating exercise-induced oxidative stress and may reduce DNA damage in athletes. While findings support its antioxidant and cytoprotective roles, further rigorous trials are needed to clarify its direct effects on DNA repair mechanisms in sports medicine. Funding: This review received no specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Registration: This review was prospectively registered in the PROSPERO database (CRD420231039805).