Cayratia trifolia leaves contain polyphenols as a natural antioxidant that can dissolve in polar solvents. This study aims to evaluate the hepatoprotective and antioxidant activity of polar extracts (ethyl acetate and 70%-ethanol) were extracted sequentially from C. trifolia leaves on male rats induced by nitrobenzene. The extracts of C. trifolia leaves were given at a dose of 200 mg.Kg -1 BW. Silymarin as a reference was given at a dose of 28.78 mg.Kg -1 BW. The extracts and Silymarin were given orally once a day for 14 days. Rats that have received ethanol extract of C. trifolia leaves showed a significant decrease in Alkaline Phosphatase (ALP), Aspartate Transaminase (AST), Alanine Transaminase (ALT), total bilirubin, and direct bilirubin. A significant decrease in malondialdehyde (MDA) levels also occurred in the rats. On histopathological examination, the extract also showed a protective effect on rat liver. Thus, it can be concluded that the sequentially extracted ethanolic extract of C. trifolia leaves has the potential as a source of natural hepatoprotective and antioxidant activity.