Psidium guajava is consumed as food and used for medicinal purposes around the world; with studies reporting its antiproliferative effects via different biochemical mechanisms, yet its modulatory effects on epigenetic modification of DNA molecules via histone deacetylases (HDACs) is largely unknown.This study was carried out to investigate the binding propensity of Psidium guajava-derived compounds on the activities of histone deacetylase 6 (HDAC6) and histone deacetylase 10 (HDAC10) for possible application as anticancer agents using in silico methods.59 guava-derived compounds and apicidin, a standard HDAC inhibitor, were docked with HDAC6 and HDAC10 using AutodockVina after modeling (SWISS-MODEL server) and validating (ERRAT (27) and VERIFY-3D) the structure of HDAC10, while their molecular interactions with the HDACs were viewed with Discovery Studio Visualizer. Prediction of binding sites, surface structural pockets, active sites, area, shape and volume of every pocket and internal cavities of proteins were done using Computed Atlas of Surface Topography of proteins (CASTp) server, while Absorption, Distribution Metabolism and Excretion (ADME) study of notable compounds was done using Swiss online ADME web tool.2α-hydroxyursolic acid, asiatic acid, betulinic acid, crategolic acid, guajadial A and B, guavacoumaric acid, guavanoic acid, ilelatifol D, isoneriucoumaric acid, jacoumaric acid, oleanolic acid, psiguadial A, B and C demonstrated maximum interaction with the selected HDACs. ADME studies reveal that although isoneriucoumaric and jacoumaric acid ranked very high as HDAC inhibitors, they both violated the Lipinski's rule of 5.This study identified 13 drugable guava-derived compounds that can be enlisted for further studies as potential HDAC6 and HDAC10 inhibitors.