Paracetamol is a popular and safe drug preferred by victims of pain or pyrexia; however, its overdose or abuse is a growing concern worldwide. Here the hepatoprotective effect of an ethnomedicinal plant Drynaria quercifolia against paracetamol‑induced toxicity in murine model is demonstrated. This fern, native to tropical countries including the Northeast India, is used by local tribes to treat inflammatory conditions. Paracetamol 500 mg/kg body weight was orally administered on alternate days for a period of 21days to mimic a chronic overdose. Drynaria quercifolia acetone extract (DQA) treatment interspaced with paracetamol significantly decreased serum biomarkers of hepatotoxicity (ALT, AST and ALP) renal toxicity (urea, creatinine), lipid peroxidation level, histological damage in liver and kidney. The protein and mRNA expressions of the transcription factor, Nrf2, and its target antioxidant genes (SOD1, CAT and GST) as well as activities of these antioxidant enzymes were downregulated by paracetamol administration but significantly recovered following the DQA treatment (Tab. 3, Fig. 5, Ref. 31). Keywords: acetaminophen/paracetamol, Drynaria quercifolia, renal toxicity, hepatotoxicity, Nrf-2.