Monoamine oxidase (EC, 1.4. 3.4) is an important biological enzyme that catalyzes the oxidation of monoamines. It is critical for the inactivation of neurotransmitters. Monoamine oxidase (MAO) exists in two isoforms; A and B. Abnormality in the activity of the monoamine oxidase B has been associated with neurological dysfunctions such as Alzheimer’s disease. An insight into the interaction of monoamine oxidase B binding site with inhibitors is crucial for the development of new pharmaceutical agents. In this study, we examined the inhibitory activity of human MAO-B and a series of bioactive ligands from Bryophyllum pinnatum as potential Monoamine oxidase B inhibitors. Computational docking analysis was performed using extra precision (XP) feature of Glide module, version 5.6. The final products of molecular docking were clustered to specify the binding free energy and Kinetic inhibition (Ki) was calculated. Docking results showed all the compounds tested (patuletin, luteolin, kaempferol and acacetin) had high binding score compared to the standard reference drugs. Specifically, patuletin, an O-methylated flavonol had the optimum binding affinity (-10.105 kcal/Mol) compared to the standard drugs selegiline (− 7.82 kcal/mol) and rasagiline (-7.82). Hydrogen bond interactions between the 3-OH of patuletin and Tyr-435 and Ile-199 of the active residues were found to have played a critical role in stabilizing the ligand bond at the active site. This present study provides salient information for the rational drug design of more potent and selective Monoamine oxidase B inhibitors in the management of neuro-degenerative disorders. Further in-vitro and in-vivo studies validating the inhibitory activity of Patuletin is highly recommended.