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The present study is planned to examine the antioxidant activity (AA) and the protective effect of the essential oil of Citrus limon (EOC) against aspirin-induced histopathological changes in the brain, lung, and intestine of female rats. For this purpose, 28 albino rats were classified to control group (group C), aspirin group (group A), EOC group (group EOC), and pretreatment with EOC and treated with aspirin group (group EOC + A). The antioxidant activities of EOC were evaluated by three different assays including reducing power, β-carotene, and scavenging of hydrogen peroxide (H 2 O 2 ). Our results found that EOC represents, respectively (0.064 ± 0.013 and 0.027 ± 00 mg Quer E/100 µL), of flavonoid and flavonol. Then, it exhibited a potential activity of reducing power (at 300 mg/mL, which was found to be 0.82 ± 0.07), β-carotene-linoleic acid (AA% = 69.28 ± 3.5%), and scavenging of H 2 O 2 (IC 50 = 0.23 ± 0.008 mg/mL). In vivo, aspirin given to rats at the dose of 600 mg/kg body weight induced histomorphological damage in brain, lung, and intestine. However, our data found that the pretreatment with EOC offered a significant protection against the injury induced by aspirin. It can be concluded that the protective effect of EOC can be due to its antioxidant activities.