In the present work, TiO2@ZnO nanoparticles (NPs) (10 wt% and 15 wt%) were decorated over poly-3-butyl thiophene (P3BT) and obtained as novel hybrid nanocomposites. The synthesized hybrid nanocomposites studied for crystalline phase, microstructure, zeta potential, water contact angle, and their antibacterial activity were evaluated by a zone of inhibition against S. bacillus and E. coli bacterial cells by disc diffusion method. The in vitro antibacterial activity results were compared with the standard drug ciprofloxacin as well as results obtained from statistical analysis. The surface dispersion and stability of the NPs were examined by water contact angle measurement and zeta potential studies. Irregular morphology was observed as TiO2@ZnO NPs concentration increased on P3BT polymer, and phase analysis revealed the mixed composition of hexagonal crystal structure. Redshift in optical absorption spectra resulted in TiO2@ZnO concentration increases on P3BT polymer. An increase in hydrophobicity with the increase in Rrms value was observed as TiO2@ZnO NPs concentration increases. It was found that P3BT:TiO2@ZnO (10 wt% and 15 wt%) hybrid nanocomposites displayed greatly improved antibacterial activity against S. bacillus and E. coli bacterial cells when compared with TiO2@ZnO NPs. The P3BT:TiO2@ZnO hybrid nanocomposites showed high stability in basic solution, better hydrophobicity, and large surface area. The results of antibacterial property studies are compared with statistical results and are in good agreement with each other exhibiting TiO2@ZnO:P3BT hybrid nanocomposites acting as a better candidate for antimicrobial therapy. [ABSTRACT FROM AUTHOR]