The current study evaluates the ameliorative action of Origanum vulgare ethanolic extract against the hepatotoxic effects of experimental doxycycline over-dose in rats. Forty male Sprague-Dawley rats with an average weight (160–200 g) were divided into four groups; group (1) the control group, administered distilled water (10 ml/kg b. wt.); group (2) administered doxycycline (39.2 ml/kg b. wt.) in distilled water; group (3) administered O. vulgar ethanolic extract (20 mg/kg b. wt.) +doxycycline (39.2 ml/kg b. wt.) in distilled water and group (4) administered O. vulgar ethanolic extract (60 mg/kg b. wt.) + doxycycline (39.2 ml/kg b. wt.) in distilled water. All rats were administrated once per day for 4weeks. Doxycycline administrated rats showed alteration in histological structure of the liver as vacuolization, necrosis, inflammation, and sinusoidal dilatations. Also increased Kupffer cells population and congestion and dilatation of central vain with fibrin thrombi filling their lumen were shown. Ultra-structurally destructed cell membrane of hepatocyte, Pyknotic and karyolitic nuclei, losses in some cytoplasmic organelles, swollen mitochondria, fragmentation of rER and discarded lysosomes were observed. All of those lesions were improved by ethanolic extract of Origanum vulgare.