Hepatocellular carcinoma is the most common primary hepatic malignancy worldwide. N-Nitroso compounds act as strong carcinogens in various animals, including primates. Diethylnitrosamine (DEN) is a well known carcinogenic substance, which induces hepatic carcinoma. The theme of the study was to evaluate the therapeutic efficacy of nanoencapsulated flavonoidal quercetin (3,5,7,3',4'-pentahydroxy flavone, QC) in combating DEN-induced hepatocarcinogenesis in rats. DEN induced a substantial increase in relative liver weights with proliferation and development of hyperplastic nodules. A significant increase in hepatocellular and nephrotoxicity indicated by serum alkaline phosphatase, aspartate transaminase, alanine transaminase, urea, and creatinine was observed in DEN-treated animals. Maximum protection from such toxicity was provided by nanoparticulated QC. Elevated levels of conjugated diene in DEN-treated rats were lowered significantly by nanoparticulated QC. Antioxidant levels in hepatic cells were reduced significantly by the induction of DEN. Nanoparticulated QC was found most potent for complete prevention of DEN-induced reduction in antioxidant levels in the liver. Upregulation of glutathione-S-transferase activity by DEN induction was reduced maximally by nanoencapsulated QC. Nanoencapsulated QC completely protected the mitochondrial membrane of the liver from carcinoma mediated by DEN injection. A significant correlation could be drawn between DEN-induced tissue reactive oxygen species generation and cytochrome C expression in the liver. Nanoencapsulated QC completely prevented the DEN-induced cytochrome C expression in the liver significantly.