OBJECTIVES: This study assessed the efficacy of oral consumption of N-acetyl cysteine (NAC) and melatonin (ML) in reducing early reperfusion injury and acute oxidative stress in patients undergoing coronary artery bypass grafting (CABG) with respect to the measurements of cardiac troponin I, lactate, malondealdehyde (MDA), and tumor necrosis factor-α (TNF-α) levels in the blood. METHODS: This study was a randomized, open-label, placebo-controlled trial. Eighty eight patients, aged between 39 to 76 years and eligible for CABG, were recruited and randomly assigned into 3 intervention groups through a simple randomization method and underwent CABG surgery. Blood samples were withdrawn from arterial line, before the induction of anesthesia (before the start of surgery), after incision (before aortic cross-clamping), during global ischemia (during aortic cross-clamping), after aortic cross-clamping (on set of reperfusion), 15 minutes after reperfusion, and after recovery at the intense care unit. The blood samples were analyzed for troponin I, lactate, MDA and TNF-α levels. RESULTS: There was no significant difference in influencing variables among the groups at the baseline. Overall mean troponin I, lactate, and TNF- α levels were significantly different between the intervention groups (all P < .001) at the recovery phase. Post-hoc pairwise comparisons showed that the differences of mean serum levels between ML and control groups were statistically significant for MDA, TNF- α, lactate, and troponin I (P < .001, P = .001, and P = .001, respectively). The differences between NAC and control groups and between ML and NAC groups were only significant for mean lactate level (P < .001). CONCLUSION: The current study revealed that ML and NAC are potent antioxidants with similar efficacy in terms of reducing CABG related cardiac injury and oxidative stress with the dosage employed for the intervention.