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The non\u2010selective \u03b2\u2010blocker propranolol demonstrated antiproliferative activity in many cancer types.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This investigation aimed to evaluate the anticancer effect of propranolol against DEN\u2010induced HCC in rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70\u2009mg\/kg body weight (b.wt.) once a week for 10\u00a0weeks, to induce HCC, and Group III (HCC\/Prop); received DEN for 10\u00a0weeks for HCC induction, then received 20\u2009mg\/kg b.wt. propranolol, intraperitoneally for four successive weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), \u03b1\u2010fetoprotein (AFP), total\u2010 and direct\u2010bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF\u20101\u03b1, IL\u20108, NF\u2010\u03baB, PGE2, TGF\u2010\u03b21, VEGF, and CD8, but significant decline of GSH, and IL\u201010 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG\u20103 were up\u2010regulated. Moreover, the protein expression of p\u2010PKC was up\u2010regulated, while that of PD\u20101 and PD\u2010L1 were down\u2010regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC\/Prop group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. 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