Zinc-dependent HDAC subtypes (ZnHDACs) exhibit differential expression in various cancer types and significantly contribute to oncogenic cell transformation, and hence are interesting anticancer drug targets. The approved pan HDAC inhibitors (PHIs) lack subtype specificity and inhibit all ZnHDACs, causing severe sideeffects. Considering the distinct tissue distribution and roles of individual ZnHDACs in specific cancer types, it is crucial to rationally design subtype-specific inhibitors (SSIs) for enhanced efficacy and reduced side-effects. There are numerous approaches already conducted for designing SSIs, especially Class I ZnHDACs, whereas Class II and III ZnHDACs are relatively unexplored and equally important in disease pathogenesis. This study attempts to decipher the specificity rendering interaction features of six different ZnHDACs by robust analyses of reported experimental data employing sophisticated computational methods like homology modelling, docking, pharmacophore analysis, and molecular dynamic (MD) simulations. Experimentally validated SSIs (activity<1000 nM) of different ZnHDACs and 8 approved PHIs were docked to 40 MD generated conformations of each ZnHDACs followed by MM-GBSA binding energy estimations. Sequences, structures, physicochemical properties, and interaction patterns of the binding sites obtained from docking were exhaustively compared to identify unique subtype-specific interaction features for each Class II ZnHDACs. To further validate the stabilities of these features, 20 ns MD simulations were performed on 12 complexes (each Class II ZnHDACs bound to one SSI and one PHI) in explicit water models. Distinct pharmacophoric patterns were observed in the binding pockets of each subtype despite high sequence similarities. Presence of amides, ketone, hydroxyl, carboxyl groups, and moieties occupying additional sub-pockets and interacting with Zn 2+, etc., in the SSIs affect the orientations of the binding site residues (BSRs) owing to subtype-specific protein- ligand interactions. Stable and unique residue interactions specific for a HDAC subtype are, e.g. E329 for HDAC4, S904 for HDAC5, W496 S563 I569 for HDAC6, M793 for HDAC9, and E302 for HDAC10. Such unique interaction features and pharmacophoric patterns can be utilized for subtype-specific ZnHDAC inhibitor design.