Objective In septic conditions, hyperinflammatory response and hepatotoxicity are caused by oxidative stress, inflammation, and apoptosis. Irbesartan (IB), an adrenergic receptor blocker, has anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effect of IB on lipopolysaccharide (LPS)- induced acute hepatotoxicity. Material and Method A total of eight rats were used in three groups; a control group; LPS group [5 mg/kg, intraperitoneally (IP)]; and LPS + IB group [5 mg/kg LPS (IP) + 50 mg/kg IB (orally)]. After sacrification, tissues from the liver and blood were obtained for immunohistochemical and biochemical evaluations, such as interleukin-1 beta (IL-1β), caspase-3 (Cas-3) alanine aminotransferase (ALT), aspartate aminotransferase (AST), oxidative stress index (OSI), total oxidant status (TOS), and total antioxidant status (TAS). Results Compared with the control group, increased AST and ALT levels in the blood, biochemically increased TOS and OSI and decreased TAS levels in the tissue, immunohistochemically increased IL-1β, Cas- 3, detected. Also, in liver tissue, histopathologically hyperemia, hemorrhage, vacuolization, and significant neutrophilia infiltration were found in the LPS group. IB administration significantly reversed all these parameters. TAS levels were increased by IB administration, whereas TOS and OSI levels were decreased (p = 0.001). IB also decreased AST and ALT values (p = 0.001). In the IB group, Cas-3 and IL-1β levels were significantly decreased by IB administration (p = 0.001). In addition, the IB ameliorated histopathological findings showed enhanced hyperaemia, haemorrhages, vacuolisation and significant neutrophilic leukocyte infiltration (p = 0.001). IB treatment attenuated LPS-induced hepatotoxicity by its antioxidant, anti-inflammatory and antiapoptotic properties. Conclusion Attenuating liver injury and restoring liver function lowers morbidity and mortality rates in patients with sepsis. IB protects liver tissue from hepatotoxicity caused by LPS thanks to its antioxidant, anti-inflammatory, and anti-apoptotic properties. Further investigation of the liver’s role in sepsis may lead to the development of new therapeutic targets and strategies. IB may be an alternative therapeutic agent for the prevention of acute hepatotoxicity during sepsis.