Abstract Histone deacetylases is a family of enzymes pivotal in regulating numerous crucial cellular processes in both plant and animal cells. Plant histone deacetylases have been considerably less investigated in comparison to their human counterparts. This study aims to provide an in-depth characterization of histone deacetylases in two model plant proteins-species Arabidopsis thaliana and Oryza sativa. Phylogenetic analysis of their relationship to known human homologs has revealed their close relation to three classes of human histone deacetylases. Notably, the highest sequence homology among histone deacetylases from different evolutionary origins was observed between human HDAC6 and A. thaliana HDA5 (43.6% homology). Structural alignment results highlighted the conservation of catalytic domains and demonstrated a high activity of inhibitors against both histone deacetylases. Ligand-protein docking studies suggested a high potency of human histone deacetylase inhibitors against A. thaliana HDA5. These findings suggest the potential efficacy of human histone deacetylase inhibitors in modulating plant histone deacetylases, thereby enhancing growth regulation, development, and stress resistance in plants.