Type 2 diabetes mellitus (T2DM) is a chronic disease, in which the body failed to regulate blood glucose level due to insulin resistance. This condition may lead to high glucose level, which could potentially causes many serious health problems associated with cardiovascular system, nerve, eye and kidney. In treatment of T2DM, enzymes such as alpha-glucosidase (AG) and dipeptidyl-peptidase IV (DPP-4) have become the main targets since these enzymes play important roles in controlling the blood glucose level in the human body. In this study, the computational approach using molecular docking simulation study was used to predict the interaction and binding affinity of polyphenol compounds from Anacardium occidentale (A. occidentale) towards the AG and DPP-4 enzymes. The results were analysed based on three parameters: binding energy value, hydrogen bond formation and hydrophobic interaction between the compound and the protein at the binding site. The result showed that myricetin interacted with AG with the lowest binding energy of -7.6 kcal/mol and formed only one hydrogen bond to the Asp327 residue. In contrast, acarbose the positive control, interacted with many residues such as Asp327, Asp443 and Asp542 with the binding energy of - 6.0 kcal/mol. As for DPP-4 enzyme, sitagliptin was predicted as the best binder out of 15 polyphenols with binding energy of -9.2 kcal/mol. At the DPP-4 enzyme druggable region, sitagliptin formed an interaction with Tyr547 residue. In conclusion, our result suggested alpha-glucosidase as the most promising enzyme interacted with polyphenol compounds with favourable inhibitory effect since it can interact better than the current anti-diabetic drug, acarbose.