The present study evaluated the in vivo hepatoprotective activity of two medicinal plants, namely, Justicia schimperiana (Hochst. ex Nees) (Acanthaceae) and Verbascum sinaiticum Benth. (Scrophulariaceae) used in Ethiopian traditional medical practices for the treatment of liver diseases. The levels of hepatic marker enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were used to assess their hepatoprotective activity against carbon tetrachloride (CCl4)-induced hepatotoxicity in Swiss albino mice. The results revealed that pretreating mice with the hydro-alcoholic extracts of both plants significantly suppressed the plasma AST ((P < 0.01) J. schimperiana; (P < 0.05) V. Sinaiticum) and ALT ((P < 0.05) J. schimperiana) activity when compared with the CCl4 intoxicated control. Among the Soxhlet extracts of each of the plants, the methanol extract of J. schimperiana showed significant hepatoprotective activity. Further fractionation of this extract using solid phase extraction and testing them for bioactivity indicated that the fractions did not significantly reverse liver toxicity caused by CCl4. However, the percentage hepatoprotection of the distilled water fraction was comparable with that of the standard drug silymarin at the same dose (50 mg/kg) as evidenced by biochemical parameters. Histopathological studies also supported these results. In vitro DPPH assay conducted on the water fraction of J. schimperiana and the Soxhlet methanol fraction of V. Sinaiticum showed that they possess moderate radical scavenging activity (IC50 = 51.2 and 41.7 μg/mL, respectively) which led to the conclusion that the hepatoprotective activity of the plants could be in part through their antioxidant action.