Abstract. Ekpo GI, Eteng OE, Ekam VS, Onyemaizu MU, Ofonime N, Blessing OE, Uduak OL, Robert AE, Ufot S, Eyong U. 2024. Hesperidin and quercetin modulate carbon tetrachloride (CCl4) induced hepatotoxicity in male rats. Asian J Nat Prod Biochem 22: 19-26. Quercetin and hesperidin are bioactive chemicals that have shown considerable promise in both conventional and herbal medicine due to their significant impact on treating various human diseases. Oxidative stress is linked to the etiology of many liver disorders. Quercetin-containing foods and fruits include kales, onions, berries, apples, cherries, and other citrus fruits like grapefruit, oranges, lemons, and mandarins. The purpose of this study is to examine the potential therapeutic benefits of quercetin and hesperidin on oxidative stress-induced hepatotoxicity using male rats treated with carbon tetrachloride (CCl4). A total of (30) male rats weighing 160-180 g were divided into 5 groups (n = 6). For twenty-one days, rats were gavaged with quercetin and hesperidin (2.4 and 2.4 mg/kg each) after being exposed to CCl4 (0.5 mg/kg). Samples were taken to evaluate several biochemical markers. Nitric oxide (NO), Hydrogen peroxide (H2O2), and Malonialdehyde (MDA) levels were assayed for oxidative damage. The enzymes alanine transferase (ALT) and alkaline phosphatase (ALP) activity were estimated to represent liver function. Glutathione peroxidase (GPx), Catalase (CAT), and Glutathione (GSH) levels were evaluated for antioxidants, and histopathology was also assessed. CCl4 increased significantly (P <0.05) the concentration of MDA, NO, H2O2, SOD, CAT, GPX, GSH, and also, the activities of ALT, ALP, and AST in serum. Following treatment with quercetin and hesperidin, significantly (P <0.05) reduced MDA, NO, H202, ALT, AST, and ALP activities and modified SOD, CAT, GPX, GSH, in rats substantially (P <0.05). Hepatotoxicity caused by carbon tetrachloride (CCl4) was protected by quercetin and hesperidin treatment. This study concludes that by recovering from ROS-mediated oxidative stress, the injection of quercetin and hesperidin helps to offset the damage that CCl4-induced hepato-renal ailments generate. Hence, quercetin and hesperidin supplements may be recommended as an adjunctive natural therapy because they can scavenge free radicals and prevent hepato-renal damage.