Alzheimer’s disease (AD), a progressive neurodegenerative health condition symptomized by dementia is characterized majorly by the accumulation of Aβ peptides and Tau hyperphosphorylation. AD also progresses as a result of oxidative stress caused by an increase in the expression of Monoamine Oxidase B (MAO-B). Therefore, possible drug candidates which can be used to inhibit the expression and activity of MAO-B, are being investigated. Plant sources are a great resource for discovering novel compounds in the treatment of disease conditions. One such plant known for its use in CNS-related conditions and has been investigated for the presence of bioactive compounds is Leonotis leonurus R. Br. (Lamiaceae). The most probable macromolecular targets of 36 bioactive compounds identified from Leonotis leonurus were predicted using swisstargetprediction.ch. Compounds predicted to target MAO-B and microtubule associated protein tau (MAPT) were then docked on the 3D molecular structure of MAO-B (PDB ID:2vrl) in a molecular operating environment (MOE) in comparison with known inhibitors. In vitro activity of the resulting compounds against MAO-B enzymes was then conducted and the results were compared. Out of the six possible compounds, vitexin was the only compound observed to have interacted with the amino acids at the active site in silico and have inhibitory activity against MAO-B in vitro.