Hepatocellular carcinoma (HCC) is a major threat to human health worldwide and development of novel antineoplastic drug is demanding task. BRM270 is a proprietary combination of traditional medicinal herbs, has been shown to be effective against a wide range of stem-like cancer initiating cells (SLCICs). However, the underlying mechanism and antitumor efficacy of BRM270 in human hepatocellular carcinoma (HCC) cells have not been well elucidated till date. Here we studied the tumoricidal effect of BRM270 on human-CD133⁺ expressing stem-like HepG-2 and SNU-398 cells. Gene expression profiling by qPCR and specific cellular protein expressions was measured using immunocytochemistry/western blot analysis. In vivo efficacy of BRM270 has been elucidated in the SLCICs induced xenograft model. In addition, 2DG-(2-Deoxy-d-Glucose) optical-probe guided tumor monitoring was performed to delineate the size and extent of metastasized tumor. Significant (P<0.05) induction of Annexin-V positive cell population and dose-dependent upregulation of caspase-3 confirmed apoptotic cell death by pre/late apoptosis. In addition, bright field and fluorescence microscopy of treated cells revealed apoptotic morphology and DNA fragmentation in Hoechst33342 staining. Levels of c-Myc, Bcl-2 and c-Jun as invasive potential apoptotic marker were detected using qPCR/Western blot. Moreover, BRM270 significantly (P<0.05) increased survival rate that observed by Kaplan-Meier log rank test. In conclusion, these results indicate that BRM270 can effectively inhibit proliferation and induce apoptosis in hepatoma cells by down-regulating CyclinD1/Bcl2 mediated c-Jun apoptotic pathway.