The synthesis and characterization of a series of 4-substituted phenyl-4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-thiones were presented. Preliminary in vitro antimicrobial activity of the compounds was assessed against a panel of microorganisms including S. aureus, E. faecalis, P. aeruginosa, E. coli, and C. albicans. Some of the compounds exhibited significantly in vitro antimicrobial activity. The pMIC values were correlated with physicochemical descriptors: Hammett substituent constants (rm and rp) and the lipophilic constant (p). One statistical significant 2D-QSAR model was obtained with parasubstituted compounds. The pMIC values were also correlated with some theoretical descriptors as independent variables and four statistical significant 2D-QSAR models were also obtained with meta-substituted compounds.