Background: The objective of the study was to compare the hepatoprotective effect of aqueous and ethanolic extracts of stem bark of Berberis lycium Royle in isoniazid (INH) induced hepatotoxicity in mice model.Methods: This randomized controlled in-vivo study conducted in male mice model from 10th April 2014 till 10th May 2014 at National Institute of Health, Islamabad. Group (C) was given normal diet and water. Group (D) was given isoniazid (50 mg/kg BW) to produce hepatotoxicity. Group (LA) and (HA) were given isoniazid (INH) plus low and high dose of aqueous extract of stem bark of Berberis lycium Royle respectively. Group (L.E) and (H.E) were given INH plus low and high dose of ethanolic extract of stem bark of Berberis lycium Royle respectively.Results: Hepatotoxicity produced by INH was shown by raised serum liver function tests (LFT’s), marked hepatocytic ballooning, significant steatosis and inflammation. Mice receiving simultaneous treatment of INH, low and high dose of aqueous extract of Berberis lycium Royle showed decrease serum LFT’s and their liver sections showed improved histological picture but more significant reduction in hepatotoxic effects were observed in animals receiving low and high doses of ethanolic extract.Conclusions: Hepatotoxicity of INH can be more fully reversed by simultaneous use of INH with ethanolic extract as it has better hepatoprotective potential in dose dependent manner as compare to aqueous extract of stem bark of Berberis lycium Royle.