One hundred fifty-two methanol and water extracts of different parts of 71 plants commonly used in Sudanese traditional medicine were screened for their inhibitory effects on hepatitis C virus (HCV) protease (PR) using in vitro assay methods. Thirty-four extracts showed significant inhibitory activity (60% inhibition at 100 mg/mL). Of these, eight extracts, methanol extracts of Acacia nilotica, Boswellia carterii, Embelia schimperi, Quercus infectoria, Trachyspermum ammi and water extracts of Piper cubeba, Q. infectoria and Syzygium aromaticum, were the most active (90% inhibition at 100 mg/mL).From the E. schimperi extract, two benzoquinones, embelin (I) and 5-O-methylembelin (II), were isolated and found as potent HCV-PR inhibitors with IC50 values of 21 and 46 mM, respectively. Inhibitory activities of derivatives of I against HCV-PR as well as their effects on other serine proteases were also investigated.