Selective monoamine oxidase B inhibitors are potential drug candidates for the treatment of Parkinson’s disease. A series of phenyl substituted isoxazole carbohydrazides was designed by structural modification of isocarboxazid, a nonselective MAO inhibitor and evaluated as inhibitors of MAO-A and MAO-B. The compounds were not able to inhibit MAO-A significantly, but most of the compounds exhibited potent inhibitory activity against MAO-B. The enzyme kinetic study of the most active compounds 5d, 5-phenyl-N′-(1-(p-tolyl)ethylidene)isoxazole-3-carbohydrazide and 5g, N′-(1-(3,4-dimethoxyphenyl)ethylidene)-5-phenylisoxazole-3-carbohydrazide displayed reversible and competitive MAO-B inhibition. In molecular modeling studies, compounds 5d and 5g exhibited strong binding affinity on MAO-B active site. The administration of compounds 5d and 5g exhibited prevention of MPTP-induced Parkinsonism as indicated by footprint analysis and horizontal wire tests. Further optimization studies are essential to exploit their potential for MAO-B associated neurodegenerative pathologies.