Drugs that target, bind, and inhibit the activities of monoamine oxidase A and B, have significantly shown to increase the monoamine content in the central and peripheral nervous system. In addition to the monoamine oxidase inhibitory effect, these drugs possess antioxidant, anti-inflammatory, anti-apoptotic, and mitochondrial activity augmenting effects. The pharmacological activity correlated with the increase in the monoamine content combined with the other neuroprotective properties makes these drugs to be useful in the treatment for the control of emotional behavior (depression & anxiety disorders) and various neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s diseases). Deprenyl (2R)-N-methyl-1-phenyl-N-prop-2-ynylpropan-2-amine) and Rasagiline (methanesulfonic acid;(1R)-N-prop-2-ynyl-2,3-dihydro-1H-inden-1-amine) are the most widely prescribed monoamine oxidase-B inhibitors. The currently available monoamine oxidase inhibitors can induce substantial adverse drug reactions, drastic drug-drug interactions, detrimental pharmacokinetic issues, and lethal hypersensitivity effects. Therefore, the current study focused on designing and synthesizing novel and potent benzoxazolinone hydrazone derivatives, in silico validation, and elucidating their effect on monoamine oxidase activity.