Rumex vesicarius is an edible herb distributed in Egypt and Saudi Arabia. The whole plant has significantvalue in folk medicine and it has been used to alleviate several diseases. Hepatocellular carcinoma (HCC), themajor primary malignant tumor of the liver, is one of the most life-threatening human cancers. The goal of thecurrent study was to explore the potent role of Rumex vesicarius extract against HCC induced in rats. Thirtyadult male albino rats were divided into 3 groups: (I): Healthy animals received orally 0.9 % normal saline andserved as negative control group, (II): HCC group in which rats were orally administered N-nitrosodiethylamineNDEA, (III): HCC group treated orally with R. vesicarius extract in a dose of 400 mg/kg b.wt daily for twomonths. ALT and AST, ALP and γ-GT activities were estimated. CEA, AFP, AFU, GPC-3, Gp-73 and VEGFlevels were quantified. Histopathological examination of liver tissue sections was also carried out. The results ofthe current study showed that the treatment of the HCC group with R. vesicarius extract reversed the significantincrease in liver enzymes activity, CEA, AFP, AFU, glypican 3, golgi 73 and VEGF levels in serum as comparedto HCC-untreated counterparts. In addition, the favorable impact of R. vesicarius treatment was evidenced bythe marked improvement in the histopathological features of the liver of the treated group. In conclusion, thepresent experimental setting provided evidence for the significance of R. vesicarius as anticancer candidate with apromising anticancer potential against HCC. The powerful hepatoprotective properties, the potent antiangiogenicactivity and the effective antiproliferative capacity are responsible for the anticancer effect of this plant.