Inspite of the wide facilities for controlling cancer growth, there are little drugs to inhibit its metastasis or prevent its angiogenesis. Discovering such natural or synthetic multi-targeted agent that might strike different targets is considered as a vital goal for tumor controlling. In a previous study, the chemoprotective effect of methanol extract of Momordicacharantia (MEMC) on albino western rats bearing hepatocarcinogenesis was evaluated. The mechanism by which MEMC exert its anticancer properties was unknown. Therefore, we aimed in this study to investigate the possible role of MEMC as anti-proliferative, anti-angiogenic and anti-metastatic agent to exert its chemoprotective effect. The study was conducted on sixty albino western rats divided into six groups, 10 rats each. Diethylnitrosamine (DENA) was injected intraperitoneally (i.p.) at a dose of 200 mg/kg body weight once, 2 weeks later rats were received carbon tetrachloride (CCl₄₎ subcutaneously (3 ml/kg/week) continued for 10 weeks. MEMC was orally produced to rats (40 mg/kg) alone, as well as before, at the same time and after DENA injection. Cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), caspase-3,-8 (Casp-3,-8), histone deacetylase (HDAC) and matrixmetalloproteinases-2,-9 (MMP-2,-9) were evaluated. MEMC treatment significantly decreased Cox-2, VEGF, HDAC and MMP-2,-9 and increased Casp-3,−8 as compared to DENAgroup,which demonstrated that the anticancer effect of MEMC may be through the inhibition of angiogenesis, proliferation and metastasis and the activation of apoptosis. The improvement in before-treated group was more pronounced than that in after- and simultaneous-treated groups, indicating thatMEMC may act as a prophylactic agent more than being a therapeutic agent.