Introduction: Paraquat is a bipyridil herbicide commonly used in modern agriculture for weed and pest control. Paraquat poisoning usually occurs through direct ingestion for suicidal intent, causing mortality as a consequence to oxidative damage, inflammation and multi-organ failure. Objectives: In this study, we investigated the ameliorative potential of Cucurbita pepo fruit on paraqaut-induced oxidative damage, inflammation, hyperlipidemia, hepatotoxicity and nephrotoxicity in rats. Methods: Rats were orally administered paraquat (2 mg/kg b.w) with or without the fruit extract (500 mg/kg b.w) or resveratrol (3.57 mg/kg b.w) co-administration for 2 weeks. Results: We found C. pepo fruit extract significantly restored paraquat-induced oxidative damage, acute inflammation and hyperlipidemia. Reduced glutathione (GSH) concentration was significantly abridged in paraquat treated group, while the concentration of GSH increases substantially across groups administered fruit extract and resveratrol. Furthermore, paraquat induced concomitant reduction in the activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD), which was restored by the fruit extract and resveratrol. However, nitric oxide level demonstrated a substantial elevation in paraquat-treated group, but restored by both the fruit extract and resveratrol. Moreover, pumpkin fruit extract and resveratrol supplementation suppressed overproduction of total cholesterol, triglycerides, low density lipoproteins, high density lipoproteins and thus, alleviated paraquat-induced hyperlipidemia. In addition, administration of C. pepo fruit extract and resveratrol ameliorated the hepatotoxic and nephrotoxic effect caused by paraquat. Conclusion: We conclude that C. pepo fruit extract and resveratrol administration ameliorated oxidative damage, acute inflammation, hyperlipidemia, hepatotoxicity and nephrotoxicity caused by paraquat ingestion.