Background Hepatocellular carcinoma (HCC) is the most common cause of mortality and morbidity related to cancer in Egypt. Garlic with its organosulfur content has the ability to lower the risk of certain cancers. Aims The aim was to see the importance of polyol pathway, redox status, p16, and RNA-binding protein tristetraprolin (TTP) in chemically induced liver injury and subsequent cancer in addition to the role played by garlic extract in chemoprevention. Materials and methods In total, 50 male rats were allocated in four groups at random. Group II received garlic extract (0.4 g/100 g body weight) by oral gavage, HCC was induced chemically in groups III and IV by single intraperitoneal dose of diethylnitrosamine (200 mg/kg body weight) and maintained on a weekly subcutaneous injection of carbon tetrachloride (3 ml/kg body weight) for 10 weeks. Group IV received garlic extract in parallel with the induction. Hepatic p16 and TTP levels were immunoassayed. Moreover, hepatic function tests, aldose reductase activity, and redox status (malondialdehyde and catalase) were evaluated, in addition to the histological evaluation. Results Aspartate aminotransferase, alanine aminotransferase, hepatic malondialdehyde level, and aldose reductase activity were increased in the HCC group upon induction. Meanwhile, serum albumin, hepatic p16 and TTP level, and catalase activity were decreased. Garlic administration in parallel with the induction reverses the obtained biochemical changes and protected against chemical induction of HCC. Histological findings confirmed the laboratory results. Conclusion Garlic could protect against diethylnitrosamine/carbon tetrachloride −induced HCC and so it may be effective in protecting the liver against chemically induced hepatocyte damage and cancer.