Epigenetic modulations by HDACs are associated with multiple disease conditions. In this context, HDACs play vital roles in the progression of diseases including several cancers, neurodegenerative diseases, inflammatory diseases, and metabolic disorders. Though several HDAC inhibitors have been established as drug candidates, their usage has been restricted because of broad-spectrum inhibition, highly toxic character, and off-target adverse effects. Therefore, specific HDAC selectivity is essential to get rid of such adverse effects. Hydrazide-based compounds have already been proven to exert higher inhibitory efficacy and specific HDAC selectivity. In this article, the detailed structure-activity relationship (SAR) of the existing hydrazide-based HDAC inhibitors has been elucidated to gather crucial information that can be utilized further for the development of promising drug candidates for combating diverse diseases in the future.