Paracetamol (P), one of the most popular and commonly used analgesic and antipyretic agents, causes hepatotoxicity in overdoses. Amlodipine (AML), an L-type calcium channel blocker, has been shown to have anti-inflammatory activity by reversing the effect of calcium in the inflammation pathogenesis. In this study, the hepatoprotective activity of AML on P-induced hepatotoxicity was evaluated. Thirty male albino Wistar rats were divided into five groups: (1) control, (2) 2 g/kg of P, (3) 2 g/kg of P + 5 mg/kg of AML, (4) 2 g/kg of P + 10 mg/kg of AML, and (5) 10 mg/kg of AML. Some liver enzymes, oxidative parameters, cytokine mRNA expressions, histopathology, and immunohistochemical studies were performed in liver and blood samples. The serum levels of alanine aminotransferase and aspartate aminotransferase and the mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta in the liver tissues were significantly increased in the group treated with P. The superoxide dismutase and glutathione parameters decreased and malondialdehyde levels increased in the livers of the rats treated with P. All these parameters were increased with both doses of the AML similar to the control group. A histopathological examination of the liver showed that AML administration ameliorated the P-induced inflammatory liver damage. In immunohistochemical staining, the expression of TNF-alpha in the cytoplasm of the hepatocytes was increased in the P group but not in other treatment groups when compared to the control. In conclusion, AML treatment showed significant protective effects against P-induced hepatotoxicity by increasing the activity of antioxidants and reducing inflammatory cytokines.