The alternative and complementary application of natural compounds has generated optimism regarding the discovery of curative and therapeutic strategies for hepatocarcinogenesis. This study examined the protective and therapeutic efficacy of Ipomoea batatas (L.) Lam. leaves extract (IbLE) extract in countering hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) at a dosage of 50 mg/kg and carbon tetrachloride (CCl4) at 2 mg/kg in male rats, in comparison with the standard chemotherapeutic agent, Doxorubicin (DOXol) at 10 mg/kg. A total of forty-eight rats were utilized and divided randomly into six groups of eight rats each. The extract was administered at a dosage based on its LD50. The results indicated that intraperitoneal (i.p.) injection of DEN/CCl4 led to oxidative stress, as evidenced by an increase in malondialdehyde (MDA) levels, significant decrease in glutathione (GSH) content, detrimental effects on total antioxidant capacity (TAC) and induction of inflammation as evidenced by elevated levels of pro-inflammatory cytokines such as IL-6, BCl2, and TNF-α, along with increased serum levels of α-fetoprotein and α-fucosidase in hepatocellular carcinoma (HCC) induced rats .These alterations were accompanied by significant elevations in hepatic function biomarkers; transaminases (AST and ALT), alkaline phosphatase (ALP), and γ-Glutamyl transferase (γ-GT). Additionally, levels of blood urea nitrogen (BUN) and creatinine were found to be increased in HCC induced rats. Our findings demonstrated that both the prevention and treatment of HCC in rats using IbLE mitigated the rise in oxidative stress biomarkers, inflammation, and liver enzyme levels. Histopathological analysis documented the biochemical findings, revealing mild vacuolar degeneration of hepatocytes, mild portal fibrosis, and slight aggregation of neoplastic cells in the liver of HCC-induced rats treated with the extract. An immunohistochemical assessment of the neoplastic liver tissue from treated rats showed moderate positive expression of proliferating cell nuclear antigen (PCNA), whereas protective rats exhibited weak positive expression of PCNA. Quantification of the total phenolics and flavonoids content were determined. It could be concluded that I. batatas may serve as a promising candidate for the prevention and treatment of neoplastic liver status and its polyphenolic content may be accountable for its activity.