A multitude of plants have been used extensively for the treatment of cancers throughout the world. The protein, α, β momorcharin has been extracted from the plant Momordica charantia (MC), and it possesses anti-cancer and anti-HIV properties similar to the crude water and methanol soluble extract of the plant. This study investigated the anti-cancer effects and the cellular mechanisms of action of α, β momocharin (200-800 μM) on 1321N1, Gos-3, U87-MG, Sk Mel, Corl-23 and Weri Rb-1 cancer cell lines compared to normal healthy L6 muscle cell line measuring cell viability using MTT assay kit, Caspase-3 and 9 activities, cytochrome c release and intracellular free calcium concentrations [Ca(2+)]i. The results show that α, β momorcharin can evoke significant dose-dependent (P < 0.05; Student's t test) decreases in the viability (increases in cell death) of 1321N1, Gos-3, U87-MG, Sk Mel, Corl-23 and Weri Rb-1 cancer cell lines compared to healthy L6 muscle cell line and untreated glioma cells. α, β momorcharin (800 μM) also evoked significant (P < 0.05) increases in caspase-3 and 9 activities and cytochrome c release. Similarly, α, β momorcharin elicited significant (P < 0.05) time-dependent elevation in [Ca(2+)]i in all five glioma cell lines compared to untreated cells. Together, the results have demonstrated that α, β momorcharin can exert its anti-cancer effect on different cancer cell lines by intracellular processes involving an insult to the mitochondria resulting in cellular calcium over loading, apoptosis, cytochrome release and subsequently, cell death.