OBJECTIVE Montelukast, a selective antagonist of type 1 cysteinyl-leukotriene receptors, has antioxidant and anti-inflammatory abilities. This study aimed to explore its hepatoprotective impact against CCl4-induced hepatotoxicity compared to a standard hepatoprotective agent, silymarin. METHODS Twenty-four albino mice were used in this study, CCl4 (1 mL/kg of 1:1 v/v CCl4:olive oil) was singly injected in mice, and montelukast was administered in a dose of 10 mg/kg. RESULTS Results revealed that montelukast significantly improved CCl4-induced alterations in both structure and function of the liver, verified respectively through histopathology and by the reduced levels of ALT, AST, ALP, and GGT upon comparison with CCl4. Also, montelukast prevented the induction of oxidative stress via decreasing hepatic MDA content and enhancing GSH levels. Moreover, montelukast produced a profound decrease in the levels of hepatic NLRP3 and its adaptor protein, ASC, and a reduction in the pro-inflammatory markers, NF-κB, IL-1β, TNF-α, and IL-6. In addition, montelukast markedly reduced liver fibrosis, as illustrated by Masson Trichrome, and the decreased hepatic levels of TGF-β and α-SMA. Furthermore, montelukast efficiently decreased apoptosis as manifested by the decreased hepatic level of Caspase 3. CONCLUSIONS Montelukast protected against CCl4-induced hepatotoxicity via exerting antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.