UNLABELLED: We evaluated the protective effects of melatonin against skeletal muscle ischemia-reperfusion injury, a significant cause of skeletal muscle damage. Ischemia-reperfusion (I/R) injury occurs due to a temporary restriction of blood flow (ischemia) followed by its restoration (reperfusion), triggering oxidative stress, inflammation, and cell death. Although current treatments are limited, melatonin's antioxidant and anti-inflammatory properties suggest potential benefits. METHODS: We studied 30 male mice divided into five groups: control, melatonin control, I/R, melatonin + I/R, and dimethyl sulfoxide control. After the designated treatments, we assessed muscle tissue for antioxidant capacity (total antioxidant status [TAS]), oxidative stress markers (total oxidative status [TOS] and malondialdehyde [MDA]), inflammation (myeloperoxidase [MPO]), and cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling [TUNEL] assay and histological analysis). RESULTS: Melatonin significantly increased antioxidant capacity (TAS) compared to all other groups. Conversely, oxidative stress (TOS) was significantly lower in the melatonin + I/R group compared to the I/R group alone. Histological analysis revealed greater necrosis, edema, inflammation, and cell death in the I/R group compared to others. Interestingly, the melatonin + I/R group exhibited significantly less damage than the I/R group, highlighting melatonin's protective effect. CONCLUSION: This study demonstrates that exogenous melatonin effectively reduces oxidative stress, inflammation, and cell death in skeletal muscle tissue subjected to I/R injury. These findings suggest that melatonin may be a promising therapeutic agent for mitigating I/R-induced complications in skeletal muscle injury.