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Background and Objectives: Carvacrol is a natural antioxidant possessing various biological properties. Diphenhydramine is a first-generation antihistamine prescribed for allergies and the common cold. Recently, investigations have shown that diphenhydramine might cause genotoxicity. Antioxidants significantly act in defending cells against oxidative induced genotoxicity. Here, we assessed the protective effect of carvacrol, as a potent antioxidant, on diphenhydramine induced oxidative genotoxicity on human peripheral blood lymphocytes. Methods: Peripheral lymphocytes were treated as followed groups: diphenhydramine concentrations (200, 500 and 1000 µg/mL), diphenhydramine in combination with carvacrol (5 µg/mL), cisplatin (0.05 µg/mL) and cisplatin in combination with carvacrol. We evaluated the formation of micronucleus (MN), known as genotoxicity occurrence indicator, to demonstrate the possibility of diphenhydramine-induced genotoxicity. Furthermore, the level of oxidative stress was assumed by cellular glutathione oxidation and lipid peroxidation. Results: The results showed that high concentrations of diphenhydramine could cause oxidative stress damages by elevating the lipid peroxidation and glutathione oxidation. The frequency of micronucleus increased after diphenhydramine exposure (p < 0.05). Interestingly, carvacrol significantly decreased frequency of micronucleus and lipid peroxidation in lymphocytes exposed to high concentration of diphenhydramine. Conclusion:  Our results further support the idea that carvacrol has beneficial effects in protecting cells against oxidative stress damages and diphenhydramine-induced genotoxicity.