Lead (Pb), a common toxicant is ubiquitously present in the environment. Chronic Pb exposure affects almost every organ system of human body including liver. Clerodendrum viscosum is a medicinal plant and its leaves are known to have hepatoprotective, anti-inflammatory, and anti-hyperglycemic activities. However, the protective effect of C. viscosum leaves against Pb-induced hepatotoxicity is yet to be studied. Therefore, this study was designed to assess the protective effect of the aqueous extract of C. viscosum leaf (Cle) against Pb-induced hepatotoxicity in experimental mice. Pb-acetate was given to Pb and Pb + Cle groups interperitoneally, and Cle was supplemented to Cle and Pb + Cle groups by oral gavage. Serum biomarkers of liver function—butyrylcholinesterase (BChE), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine transaminase (ALT), antioxidant enzyme activities in hepatic tissue—superoxide dismutase (SOD), reduced glutathione reductase (rGR) and catalase (CAT), levels of transcription factor—nuclear factor erythroid 2-related factor 2 (Nrf2), and inflammatory marker—interleukin-6 (IL-6) were analyzed. Additionally, histological analyses of hepatic tissues of all groups of experimental mice were performed. Pb-treatment significantly increased ALP, AST, and ALT activities and decreased BChE activity compared to control mice. The antioxidant enzyme (SOD, rGR, and CAT) activities and expression of Nrf2 level were significantly (p < .05) decreased, while IL-6 level was significantly (p < .05) increased in the hepatic tissue homogenates of Pb-treated mice compared to the control group. Furthermore, histological examination revealed the disruption of hepatic tissue integrity in Pb-treated mice. Notably, supplementation of Cle provided significant protection against the changes in the activities of liver function biomarkers and antioxidant enzymes, levels of Nrf2 and IL-6, and disruption of hepatic tissue by Pb. Taken together the present study suggests that Cle ameliorates the hepatic toxicity caused by Pb.