Liver is a precious organ to maintain body life. Hepatotoxicity is a worldwide health problem that is still a challenge for research. Although countless pharmaceutical drugs and herbal compounds were screened for their hepatoprotective effects, the death from hepatotoxicity is increasing. Thus, there is continuous necessity of searching for the hepatoprotective effect of commonly used drugs. Accordingly, our aim was to examine a hepatoprotective potential for the antihypertensive drug, verapamil, and searching for new insights underlie its protective mechanism. Four groups of adult male rats were randomly arranged as controls, thioacetamide (TAA) hepatotoxic, and TAA + verapamil treated. Serum liver enzyme, hepatic antioxidant, lipid peroxidation, and inflammatory parameters were assessed. Gene relative expression for heme oxygenase-1 (HO-1), nuclear factor-erythroid 2-related factor 2 (Nrf2), phosphoinositide 3-kinase (PI3K), and serine/threonine-specific protein kinase (Akt) were quantified in hepatic tissue. TAA caused hepatic injury evident both histopathologically and biochemically by a decrease in all gene expressions. Verapamil alleviated the injury via its antioxidant and anti-inflammatory effects that were suggested to be via upregulation of the previous gene expressions. In conclusion, the calcium channel blocker, verapamil, that is used widely as antihypertensive exhibits a valuable hepatoprotective effect. The protection partially rests on activation of Nrf2/HO-1 and PI3K/Akt pathways.