The ethanol extracts of Piper retrofractum were investigated for antioxidant and hepatoprotective activity. Hepatoprotective activity against paracetamol-induced acute hepatotoxicity was estimated in Sprague-Dawley rat. In DPPH free radical assay the root and stem extracts showed IC₅₀ values at 133 and 91 µg/mL, respectively, while ascorbic acid at 14 µg/mL. Extracts also exhibited hydroxyl radical scavenging activity and reducing power. HPLC-DAD analysis indicated the presence of some polyphenolic compounds. Treatment of extracts significantly reduced the elevated serum levels of GPT (P < 0.01), GOT (P < 0.01) and bilirubin (P < 0.001). Both extracts restored the reduced level of total proteins and albumin. A significant increase in HDL-c but decrease in LDL-c level was observed compared to induced control. In histopathological study of liver sections, both extracts showed minimal to mild multifocal and diffuse granular degeneration and mild to moderate lobular disarray compared to control group. Results suggest that both extracts can prevent paracetamol induced hepatotoxicity.