Apteranthes europaea (Guss.) Murb. subsp. maroccana (Hook.f.) Plowes (A. europaea) is a medicinal plant widely used in traditional medicines to treat various diseases including hepatic pathogenesis. This study was conducted to evaluate the protective effect of chemically characterized polyphenol-rich fraction from A. europaea on carbon tetrachloride-induced liver injury in mice. The chemical characterization of A. europaea polyphenol-rich fraction was carried out using HPLC-DAD (high-performance liquid chromatography (HPLC) with a diode-array detector (DAD)). Carbon tetrachloride (CCl4) was used to induce liver injuries in mice as described in previous works. A polyphenol-rich fraction from A. europaea was used at a dose of 50 mg/Kg to study its hepatoprotective effect. Next, histopathological and biochemical alterations were investigated. The HPLC analysis revealed the presence of several phenolic compounds: gallic acid, methyl gallate, rutin, ferulic acid, and resorcinol. Regarding the mice treated with a polyphenol-rich fraction from A. europaea up to 50 mg/Kg and carbon tetrachloride, no significant biochemical nor histological alterations occurred in their liver; meanwhile, serious biochemical and histopathological changes were noted for liver recovered from the mice treated with carbon tetrachloride only. In conclusion, A. europaea extract is a promising source of hepatoprotective agents against toxic liver injury.