The limitations associated with conventional antibacterial therapies and the subsequent amplification of multidrug-resistant (MDR) microorganisms have increased, necessitating the urgent development of innovative antibacterial techniques. Accordingly, nanoparticle-mediated therapeutics have emerged as potential candidates for antibacterial treatment due to their suitable dimensions, penetration capacity, and high efficiency in targeted drug delivery. However, although nanoparticle-based drug delivery systems have been demonstrated to be effective, they are limited by their overuse and unwanted side effects. Thus, to overcome these drawbacks, stimulus-responsive antibiotic delivery has been extended as a promising strategy for site-specific restricted drug exemption. Nano-formulations that are triggered by various stimuli, such as intrinsic, extrinsic, and bacterial stimuli, have been developed. Thus, by harnessing the physicochemical properties of various nanoparticles, the selective release of therapeutic cargoes can be achieved through the application of a variety of local stimuli such as light, sound, irradiation, pH, and magnetic field. In this review, we also highlight the progress and perspectives of stimulus-responsive combination therapy, with special emphasis on the eradication of MDR strains and biofilms. Hence, this review addresses the advancement and challenges in the applications of stimulus-responsive nanoparticles together with the various future prospects of this technique.