Salvia officinalis L., commonly known as sage and belonging to the Lamiaceae family, is a medicinal herb indigenous to the Mediterranean region. It is celebrated for its diverse pharmacological properties and traditional uses in folk medicine, particularly in addressing hepatotoxicity. Cisplatin (Cis), a potent chemotherapeutic agent widely employed in cancer treatment, is recognized for its efficacy but often accompanied by adverse effects, including hepatotoxicity. The aim of this study was to assess whether an ethanolic S. officinalis extract (ESOE) could provide protection against Cis-induced hepatotoxicity in an experimental rat model. The ESOE was prepared using standard extraction techniques, and its chemical constituents were elucidated through UPLC-ESI-MS/MS analysis, revealing the presence of bioactive compounds such as alkaloids, phenolic compounds, and flavonoids, which are associated with various therapeutic effects, including hepatoprotection. Adult male albino rats were allocated into four groups: control, ESOE (250 mg/kg), Cis (7.5 mg/kg), and ESOE (250 mg/kg) + Cis (7.5 mg/kg). The treatment duration lasted 21 days, with Cis administration on the 22nd day. Twenty-four hours post-Cis administration, blood and liver samples were collected for analysis. Cis-induced hepatotoxicity was evidenced by alterations in hematological parameters, including erythrocyte, thrombocyte, leukocyte, and lymphocyte counts, alongside elevated serum levels of liver enzymes (ALT, LDH, AST, ALP, and GGT), indicative of liver damage. Furthermore, Cis exposure resulted in increased hepatic malondialdehyde (MDA) and Nitric oxide (NO) levels, oxidative stress markers, coupled with decreased levels of reduced glutathione (GSH), a non-enzymatic antioxidant, and histopathological changes in liver tissue, characterized by necrosis and inflammation. Additionally, Cis treatment led to elevated levels of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), TNF-α, and IL-6, indicating oxidative stress and inflammation. Remarkably, pretreatment with ESOE ameliorated these Cis-induced hepatotoxic effects, as evidenced by improved hematological parameters, reduced liver enzyme activities, alleviated oxidative stress, and ameliorated histopathological alterations. The observed hepatoprotective effects of ESOE against Cis-induced liver injury may be attributed to its antioxidant and anti-inflammatory properties, highlighting its potential as a natural therapeutic agent in mitigating chemotherapy-associated hepatotoxicity.