A series of 2,6-diaryltetrahydropyran-4-one thiosemicarbazones (11-27) were synthesized and characterized for evaluation of potential antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Bacillus subtilis and Klebsiella pneumonia and antifungal activity against Cryptococcus neoformans, Candida albicans, Rhizopus sp., Aspergillus niger and Aspergillus flavus were evaluated. Compounds 21 and 22 showed maximum inhibition potency at low concentration (6.25 μg/ml) against P. aeruginosa. For antifungal activity, 20 and 21 were effective against C. neoformans and 22-24 against C. albicans at minimum concentration. Further, the results of QSAR studies of these synthesized compounds indicated the importance of weakly polar component of surface area, hydrophobicity and ionization potential parameters in defining their antimicrobial activity.