Acetaminophen, also known as N-acetyl-para-aminophenol (NAPAP), is a traditional antipyretic and analgesic that is used extensively around the world to treat colds and fevers. However, a NAPAP excess causes rapid, severe liver and kidney damage. The goal of the study was to examine the protective effects and determine the mechanisms of action of MPHE, hesperidin, and quercetin in NAPAP-induced hepatorenal damage in Wistar rats. Male Wistar rats received a 0.5 g/kg oral supplement of NAPAP every other day for a period of four weeks. During the same period of NAPAP supplementation, MPHE (50 mg/kg), quercetin (20 mg/kg), and hesperidin (20 mg/kg) were administered to rats receiving NAPAP. MPHE, quercetin, and hesperidin treatments significantly improved liver function in NAPAP-supplemented rats. The high serum levels of aminotransferases, alkaline phosphatase, lactate dehydrogenase, and γ-glutamyl transferase as well as total bilirubin were significantly reduced, while the levels of suppressed serum albumin were significantly increased, demonstrating this improvement. Treatments utilizing these natural substances significantly enhanced kidney function as seen by a considerable decline in the increased blood levels of urea, uric acid, and creatinine. Additionally, the injection of MPHE, hesperidin, and quercetin resulted in a decrease in the quantity of lipid peroxides while increasing the activities of superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase in the liver and kidneys. The treatments markedly abated the NAPAP-induced liver and kidney histological perturbations and reduced the NAPAP-induced serum tumor necrosis factor-α level and liver and kidney proapoptotic protein 53 and caspase 3 expressions. Otherwise, serum interleukin-4 level significantly increased by treatments. The MPHE, hesperidin, and quercetin treatments resulted in marked decrease in liver and kidney histopathological scores including inflammation, necrosis, apoptosis, and congestion. In conclusion, the MPHE, quercetin, and hesperidin may induce hepatonephropreventive impacts in NAPAP-supplemented rats via enhancing the antioxidant defense system, anti-inflammatory activity, and antiapoptotic action.