The sulforhodamine B (SRB) assay was used to assess the cytotoxicity of the aqueous (AqEx) and ethanolic (AlEx) extracts, respectively, of the aerial parts of Cleome droserifolia (Forssk.) Del. against two human cancer cell lines, breast (MCF7) and colon (HCT116) adenocarcinoma. AqEx exhibited higher cytotoxic activity, thus its four subfractions, namely n-hexane (HxFr), chloroform (ClFr), ethyl acetate (EtFr), and n-butanol (BuFr) fractions, were also tested. Purifi cation of the more active ClFr and EtFr yielded nine compounds. Six terpenoids, guai-7(11),8-diene (C₁), 1-hydroxy-guai-3,10(14)-diene (C₂), 18-hydroxydollabela- 8(17)-ene (C₃), (24E)-stigmasta-5,8-dien-3β-ol (C₄), teucladiol [1α,5β-guai-10(14)- ene-4β,6β-diol] (C₅), and buchariol (4,10-epoxy-6α-hydroxyguaiane) (C₆), were isolated from ClFr and three fl avonol glycosides, isorhamnetin-3-O-β-D-glucoside (F₁), quercetin- 3`-methoxy-3-O-(4``-acetylrhamnoside)-7-O-α-rhamnoside (F<sub>2</sub>), and kaempferol-4`-methoxy- 3,7-O-dirhamnoside (F₃), were isolated from EtFr. Compounds C₃ and F₂ are new in nature. The isolated compounds were identifi ed using various spectroscopic methods (UV, IR, 1H NMR,13C NMR, HMQC, HMBC, and COSY). Compounds C₁, C₃, F₂, and F₃ showed significant cytotoxic activities against the two tested cell lines comparable to those of the anticancer drug doxorubicin^®. The new compound C₃ was the most active as it had the lowest IC₅₀ values, (1.9 ± 0.08) and (1.6 ± 0.09) μg/ml corresponding to 6.5 and 5.4 μM, against MCF7 and HCT116 cells, respectively