Andrographis paniculatais a herbal plant used in traditional medicinal approaches to treat various ailments and diseases. Methotrexate (MTX) is a clinically used immunosuppressant and anticancer drug. One of the increasing concerns with MTX use is liver toxicity. The aim of this study is to investigate the potential effect of aqueous leaf extract ofAndrographis paniculataagainst methotrexate-induced hepatotoxicity. Wistar albino rats were grouped into five groups, and the drugs were administered. MTX (20 mg/kg b.w.) was intraperitoneally injected into rats on the ninth day alone. Aqueous leaf extract ofAndrographis paniculata(500 mg/kg b.w./day) was orally administered for 10 days. We confirmed the beneficial effect of aqueous extracts ofAndrographis paniculataon restoring the hepatic enzyme markers, lipid profile, antioxidant level, anti-inflammatory marker (IL-10), anti-apoptosis (bcl-2), significant suppression of inflammatory cytokines (TNF-α, and IL-6), apoptosis marker (caspase 3) and cellular tissue damage caused by MTX. Overall, we revealed thatAndrographis paniculatareduces critical aspects of oxidative stress, inflammatory processes, and apoptosis, thus protecting against methotrexate-induced hepatotoxicity.