Synthetic antimetabolite methotrexate (MTX) is widely used therapeutically, but its clinical use is constrained by liver damage, often resulting from oxidative stress. The purpose of this study is to examine the hepatoprotective properties of Polygonum aviculare against MTX-induced liver damage in Wistar rats. Ethanolic and aqueous extracts were prepared from aerial parts of P. aviculare. Adult healthy rats were divided into five groups and given the following treatments over a 10-day period: Group I (Control-Untreated), Group II (Methotrexate at 40 mg/kg Body weight, intraperitoneally), Group III (Methotrexate + Silymarin at 100 mg/kg, orally), Group IV (Methotrexate + ethanolic extract at 100 mg/kg, orally), and Group V (Methotrexate + aqueous extract at 100 mg/kg, orally). Serum levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine transaminase (ALT) significantly increased, indicating liver damage from MTX. Pre-treatment with P. aviculare extracts has significantly reduced these elevations, and this result has been additionally confirmed by the histological findings. The serum parameters ALT, AST, and ALP were measured using blood samples.