Background Hepatocellular carcinoma (HCC) is the third principal reason for tumor-linked fatalities globally. There is no effective cure for HCC due to rapid progression and poor prognosis. Rosmanol (RM) is a phenolic diterpene antioxidant that exhibits anti-inflammatory and anticancer properties.Purpose This research aims to examine the chemopreventive efficacy of RM on the PI3K/Akt pathway as a potential mechanism for its protective effect against N-diethylnitrosamine (DEN)-induced HCC.Materials and Methods Wistar albino male rats were separated into four sets: normal control (NC); DEN-induced HCC model; DEN+RM (40 mg/kg bw); and RM (40 mg/kg bw) alone. To evaluate the chemopreventive mechanism, we assessed the change in body weight, liver weight, hepatotoxicity markers, antioxidant enzymes, lipid peroxidation, proliferation proteins, cytokines, histopathology, and western blot.Results and Conclusion Our data revealed that RM could reduce the loss of body weight, liver weight, toxicity enzymes, oxidative stress, inflammation, and restructuring of the hepatocellular architecture against DEN-stimulated HCC rats. RM-alone treated rats exhibited comparable activity with NC. Furthermore, RM attenuates PCNA and cyclin-D1 protein expression by the regulation of the PI3K/Akt pathway. The possible chemopreventive activities of RM may be owing to its antioxidative, anti-inflammatory, and antiproliferative effects. Thus, RM may aid as an innovative remedial agent for HCC treatment.