BACKGROUND Cancer is a serious clinical problem to the health care system. Anticancer drugs have been extracted from plants containing phenolic compounds. Leucenia species (Fabaceae) contain a variety of bioactive components of numerous biological and pharmacological properties. OBJECTIVE This study explored the constitutive polyphenols of Leucenia leucocephala Lam. growing in Egypt and evaluated the antioxidant and cytotoxic activity. METHODS Chemical structures of the isolated compounds from the leaves of L. leucocephala were established by spectral techniques (UV, (1)H, and (13)C NMR, MS). RESULTS Chromatographic separation of 80% MeOH extract of the leaves of L. leucocephala have resulted in a novel flavonoid-galloyl glycoside [myricetin 3-O-(2',3'4'-tri-O-galloyl)-α-L-rhamnopyranoside] with three known polyphenolic compounds isolated for the first time from this species (apigenin 7-O-β-D-glucuronopyranoside methyl ester, luteolin 7-O-β-D-glucuronopyranoside methyl ester, and 1,3,6-tri-O-galloyl-β-D-glucopyranose) and seven known previously isolated compounds. Also, 80% methanol extract exhibited high antioxidant activity (SC(50) = 3.94 µg/ml), which is correlated with its phenolic content. The extract also showed cytotoxic activity against Hep G2 (IC(50) value 1.41 µg/ml) confirming its anticancer activity against hepatocellular carcinoma. Among the tested compounds (4-8) for antioxidant property, compound 7 was the most active compound (SC(50) = 2.49 µg/ml). Also compounds 7 and 8 exhibited high cytotoxic activity (IC(50) = 2.41 and 2.81 µg/ml, respectively). CONCLUSIONS These findings demonstrate that the leaves of L. leucocephala contain a considerable amount of polyphenolic compounds with high antioxidant properties, thus it has great potential as a source for natural health products.