The design of stable, efficient and processable bactericidal materials represents a significant challenge for combating multidrug-resistant bacteria in a variety of engineering fields. Herein, we report a facile strategy for the preparation of hollow polymeric nanosphere (HPN)-supported imidazolium-based ionic liquids (denoted as HPN-ILs) with superior antimicrobial activities. HPN-ILs were tailored by moderate Friedel−Crafts polymerization followed by the sequential covalent bonding of imidazole and bromoalkene. The resultant HPN-ILs have uniform hollow spherical morphology, an adequate surface area, and excellent physicochemical stability. Furthermore, they are highly active against both Gram-positive and Gram-negative bacteria and exhibit typical time/dosage-dependent antibacterial activities. The rational combination of porous HPNs and antibacterial ILs to generate an all-in-one entity may open new avenues for the design and fabrication of efficient bacteriostatic agents. Moreover, HPN-ILs have good biocompatibility and can also be loaded onto diverse matrices, and thus could extend their practical bactericidal application in the potential biomedical-active field.