The effect of ethanol extract from aerial parts of Cleome droserifolia was investigated against carbon tetrachloride induced liver injury. The hepatoprotective activity was evaluated through the quantification of biochemical parameters and confirmed using histopathology analysis. Efficient hepatoprotective effect was achieved by crude extract, fractions and some pure compounds. The phytochemical studies showed that the petroleum ether fraction afforded two known guaiane sesquiterpenes buchariol (1) and teucladiol (2) in addition to daucosterol (β-sitosterol glucoside) (3). The CHCl3 fraction afforded three known flavonoid derivatives; 5,3′-dihydroxy-3,6,7,4′,5′-pentamethoxyflavone (4), 5′-hydroxy-3,6,7,3′,4′,5′-hexamethoxyflavone (5) and luteolin (6) and a known dolabellane diterpene (1R,2R,3E,7E,11R,12S)-2-O-acetyl-16-O-(3-hydroxy-3-methylglutaryl)-dolabella-3,7-dien-2,16,18-triol (7). The active parts of the MeOH fraction afforded the previously unreported 3′-methoxy-3,5,4′-trihydroxy flavone-7-neohesperidoside (8) and a known megastigmane norterpene; (6S,9R)-roseoside (9).