Background: Leaves of Costus pictus D. Don, (insulin plant) are used as dietary supplement for the treatment of diabetes. Objective: The antidiabetic activity of this plant is well documented, but its activity on different cell types and mechanism remains unknown. Thus, the present study evaluates the cytotoxicity of C. pictus methanolic extract (CPME) against various cancer and normal cells. Materials and Methods: Dried leaves of C. pictus were extracted using methanol and were subjected to histone deacetylase (HDAC) inhibition and toxicity studies. Results: The CPME displayed a selective toxicity toward tested cancer cells in a dose- and time-dependent manner. CPME exhibited significant cytotoxicity on Liver hepatocellular carcinoma cells (Hep G2) (half maximal inhibitory concentration IC50 = 6.7 μ g/ml). Since CPME demonstrates both antidiabetic, anticancer activity, and HDAC enzyme play a detrimental role in both the complications, we have evaluated the CPME-induced HDAC regulation on Hep G2 cell lines. CPME showed a notable HDAC inhibition (55%). Furthermore, CPME did not show any genotoxicity or membrane instability at the tested concentrations. Conclusion: CPME demonstrates selective cytotoxicity toward tumor cells at a lower concentration through HDAC inhibition.