A series of substituted hydrazide derivatives have been synthesized and screened for their in vitro antimicrobial activities against five representative microorganisms. The results of antimicrobial study indicated that the presence of electron withdrawing groups on the benzoic acid moiety improved antimicrobial activity. Further, the presence of heterocyclic ring furan does not improve the antimicrobial activity of substituted hydrazides. To understand the relationship between physicochemical parameters and antimicrobial activity of substituted hydrazide derivatives, QSAR investigation was performed by the development of one-target and multi-target models. The multi-target model was found to be effective in describing the antimicrobial activity of substituted hydrazides in comparison to the one-target models. Further, it indicated the importance of the topological parameter, valence third order molecular connectivity index ((3)chi(v)) and the electronic parameter, energy of highest occupied molecular orbital (HOMO) in describing the antimicrobial activity of substituted hydrazides.