Background: Aceclofenac (ACF), a widely used nonsteroidal anti-inflammatory drug, has been associated with a number of severe cases of clinical hepatotoxicity. Terminalia bellirica, an evergreen tree, is known to have several ethnomedicinal uses including antioxidant and hepatoprotective effects. Hence T. bellirica fruit extracts and its phytoconstituent ellagic acid (EA) are expected to provide protection against oxidative stress and liver damage produced by long-term use of ACF., Aim: To evaluate the antioxidant and hepatoprotective activities of T. bellirica fruit extracts and EA against ACF-induced toxicity in albino Wistar rats., Methods: The in vitro antioxidant activities of T. bellirica fruit ethyl acetate and aqueous extracts were measured by metal ion chelation and nitric oxide radical scavenging assays. The in vivo antioxidant and hepatoprotective effects of T. bellirica extracts (200 mg/kg) and EA (40 mg/kg) in ACF-induced hepatotoxic rats were assessed in serum and liver tissue after oral administration for 21 d. Silymarin (40 mg/kg) was used as a standard control. Oxidative stress markers in the blood (ferric reducing ability of plasma and lipid peroxidation inhibition) and liver tissues (superoxide dismutase, catalase and malondialdehyde) were analyzed using standard protocols. Liver function markers such as alkaline phosphatase, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, lactate dehydrogenase, γ-glutamyl transferase, creatinine, total protein, and uric acid were evaluated in rat serum., Results: The T. bellirica fruit ethyl acetate extract exhibited superior metal ion chelating and nitric oxide radical scavenging abilities during in vitro antioxidant assays as compared to aqueous extracts. Oral administration of ACF in rats (15 mg/kg) for 21 d produced oxidative stress and adversely affected liver function suggesting liver injury. Treatment with extracts (ethyl acetate and aqueous), EA and silymarin accounted for a significant reduction in the adverse effects of ACF on oxidative stress and liver function markers in serum and hepatic tissue in rats. Histopathological evaluation of the liver indicated that the extracts and EA significantly decreased the degree of liver damage. The in vivo efficacy of EA was higher than T. bellirica fruit extracts. Of these extracts, ethyl acetate extract revealed comparatively better antioxidant and hepatoprotective activity., Conclusion: Ellagic acid and T. bellirica fruit extracts exhibited considerable hepatoprotective and antioxidant activities in long-term ACF-treated rats., Competing Interests: Conflict-of-interest statement: The authors declare that there are no conflicts of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)