Polycomb group (PcG) proteins have been observed to maintain the pattern of histone by methylation of the histone tail responsible for the gene expression in various cellular processes. The PcG protein consists of two multicomplex, Polycomb Repressive Complexes 1 and 2, which includes Enhancer of zeste homolog 2 (EZH2) acting so that the histones silences tumor suppressor genes. Overexpression of EZH2 results in hyper activation observed in various forms of cancer, for instance, prostate and breast cancer. In the past decade, potent inhibitors for EZH2 have been discovered. However, reports of natural compounds for targeting EZH2 is significantly less. The druglikeness and pharmacokinetic properties of several natural compounds were analyzed and the compound with top inhibitory property was studied by molecular docking. A GLIDE score of −8.223 kcal/mol with stable interaction between the protein and ligand was observed for a simulation of 50 ns. This suggests the use of selected compound as an effective inhibitor for EZH2.