Background and Objective. Clerodendrum wallichii Merr leaves are traditionally used for the treatment of fever, skin infections, inflammation, diarrhea, and dysentery. However, its pharmacological investigation is scarce and no data found on its effect on the liver. We aimed to evaluate the protective effect of Clerodendrum wallichii methanol extract (MECW) against ethanol-induced liver injury in Sprague-Dawley rats. Materials and Methods. An oral acute toxicity study was carried out following OECD guidelines. Hepatotoxicity was induced by the administration of ethanol for 4 weeks. Hepatic enzymes and oxidative stress biomarkers were determined using commercial diagnostic kits. Results. Treatment of rats with MECW (800 mg/kg) showed the highest reduction of body weight (4.76 ± 0.372 vs. 16.92 ± 0.846) and liver weight (3.06 ± 0.128 vs 5.55 ± 0.311). Treatment of rats with MECW at 200, 400, 600, 800, and 1000 mg/kg significantly (∗∗p<0.01) reduced SGPT. Similarly, serum SGOT and ALP were significantly decreased by MECW (200, 400, 600, 800, and 1000 mg/kg). All used doses of MECW significantly increased antioxidant enzymes GSH and SOD. MECW (600 and 800 mg/kg) significantly promoted CAT levels in liver tissues; whereas, it significantly diminished oxidative biomarker, MDA. Histopathological observations of the liver showed improvement in the architecture of hepatic cells having signs of protection with a reduced number of inflammatory cells, vascular degeneration and congestion, cellular degeneration, necrosis, and significant reduction of fatty cells accumulation. Acute toxicity study resulted in the well-tolerability and safety of used doses of MECW (200–1000 mg/kg) in rats. Conclusion. Our study clearly demonstrated the hepatoprotective effect of Clerodendrum wallichii extract against ethanol-induced liver injury in the laboratory rats model.