© 2022, The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.The aim of this study was formulating a new-generation antibacterial dressing in a form of polymer-based hybrid nanofiber-nanoparticles, effective on Gram-negative and Gram-positive bacteria using silver sulfadiazine (SSD), an FDA-approved topical antibiotic. In this study, SSD nanoparticles were prepared with chitosan for taking the advantage of antibacterial and wound healing properties. Chitosan nanoparticles of SSD were prepared by using tripolyphosphate (TPP) or sulfobutylether-β-cyclodextrin (SBE-β-CD) as crosslinkers via ionic gelation method and then loaded to PVP-K30 and PVP-K90 nanofibers to obtain polymer-based nanofiber-nanoparticles. SSD-loaded chitosan nanoparticles prepared with SBE-β-CD had lower particle size (359.6 ± 19.9 nm) and polydispersity index (0.364 ± 0.113) as well, indicating a more desired particle size distribution but lower encapsulation efficiency (56.04% ± 4.33). It was found that loading drug in SBE-β-CD crosslinked nanoparticles and dispersing in nanofiber matrix lowered SSD release compared to TPP crosslinked nanoparticle-loaded nanofibers. Drug release obtained by both TPP or SBE-β-CD crosslinked nanoparticle-loaded PVP-K30 nanofibers is significantly higher than nanoparticle-loaded PVP-K90 nanofibers, indicating that SSD release was mainly affected by polymer type. SSD nanoparticle-loaded PVP-K30 nanofibers were found to be effective against Gram-negative (Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii) and Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis). SSD release was sustained by PVP-K90, resulting in lower antibacterial efficiency especially against Gram-positive bacteria. PVP-K30-based nanofiber-CS nanoparticle hybrids offer a new platform by combining and improving advantages of nanofibers and nanoparticles for obtaining controlled drug release and antibacterial efficacy.