Sulfur mustard (SM) is an important chemical warfare agent. The mechanism of SM toxicity still has not been fully recognized. However, oxidative stress and following the damaging of macromolecules in the human body is considered one of the crucial steps in SM toxicity. Rats intoxicated with pure (i.e., distilled) SM were used as a model organism. The doses, 0 (control), 5, 20, and 80 mg/kg of body weight, were applied intradermally. A hormone with strong antioxidant potency, melatonin, was applied (25 and 50 mg/kg, subcutaneously) into the other group of rats exposed with the same doses of SM. Total plasma protein, ferric-reducing antioxidant power (FRAP), thiobarbituric-acid-reactive substances (TBARS), and plasma protein carbonyls were assayed in blood plasma. A significant decrease of total plasma proteins was found for control, and the lowest dose of SM was treated with melatonin. Melatonin was also able to enhance the production of low-molecular-weight antioxidants, as the SM-intoxicated rats had significantly (P ≤ 0.01) increasing FRAP levels after intoxication with SM in doses of 20 and 80 mg/kg, when compared to the control treated with melatonin. Melatonin also decreased TBARS level, representing reduced lipid peroxidation (LPO). However, LPO seems to be of less importance for SM toxic impact. The more reliable parameter was the level of total plasma protein carbonyls. The carbonyl levels were significantly increased due to SM, and the carbonylation was slowed due to melatonin intake. In conclusion, melatonin seems to be a prospective compound in reducing SM toxicity impact in the rat.