Plants are valuable source of a variety of drugs for human diseases including cancer. Most of Egyptian plant species have not been studied for their biological activities. In the continuing effort to screen Egyptian plants for anticancer activity, 16 plants were collected from different areas in Egypt. Plants extracts were tested for their cytotoxic activity against human hepatocellular carcinoma cell line (Hep-G2). According to the National Cancer Institute NCI protocols, Sesamum indicum and Aberia caffra are considered as strongly active plants against Hep-G2 cell line (less than IC50 20 μg/ml) while Conocarpus erectus and Bombax ceiba showed moderate cytotoxicity (IC50 21 -50 μg/ml). The rest of tested plant extracts showed no activity. Bio-guided isolation of petroleum ether extract of Sesamum indicum, resulted in isolation and identification of two active compounds, methyl linoleate and sesaminol (IC50 = 14.7 and 17.9 μg/ml, respectively). Moreover, column chromatographic separation of alkaloids containing fraction from Aberia caffra resulted in the isolation of an active compound with IC50 5.4 μg/ml which was identified as Aberiamine. In-silico analysis of Hep-G2 cytotoxic compounds revealed their ability to bind with caspase-3 via hydrogen bonds and/or arene-cation interactions to initiate apoptosis of cancer cells. In vivo antitumor study against diethylnitrosamine (DEN)-induced liver hepatocellular carcinoma in rats of Sesamum indicum showed improvement in liver enzymes serum level, Alpha-fetoprotein (AFP) hepatic content and in histopathological findings. On the other hand, treatment with Aberia Caffra showed minimal improvement in liver enzymes, AFP hepatic content and histopathological findings.