Cordia rothii Roem. & Schult. possesses various beneficial effects and is traditionally used in folk medicine against liver diseases but its molecular mechanism remains unclear. Antioxidant and hepatoprotective effects of Cordia rothii methanolic fraction (CRMF) were investigated in CCl₄-induced liver injury. Antioxidant effects were evaluated using DPPH assay, ferric thiocyanate (FTC) assay, and HepG2 cells. A qualitative analysis of phytochemicals was carried out by gas chromatography-mass spectrometry (GC-MS). The hepatoprotective effects of CRMF were assessed against CCl₄-induced liver damage in rats. Our results showed that CRMF significantly increased cell viability against CCl₄-induced HepG2 cells. The in vivo results showed that CRMF significantly reduced the level of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, hepatic antioxidant enzymes, including superoxide dismutase, malondialdehyde, and increased glutathione level. Normal hepatocyte integrity and microstructures were observed in histopathological results. Furthermore, the mRNA level of inflammatory mediators including interleukon (IL)-1β, IL-6, TNF-α, nuclear factor kappa B (NF-_KB), IL-10 and nuclear factor-erythroid factor 2-related factor 2 (NrF2) were reverted in CRMF pretreatment groups. Thus, CRMF exhibited strong antioxidant, and hepatoprotective activities, which may involve Nrf2–NFκB pathways.