Nowadays, there are concerns about the inadequacy of new antimicrobials and the rise of antimicrobial resistance. Hence, novel antibacterial agents need to be discovered. In this respect, the use of nanoparticles (NPs) seems promising. Zinc oxide nanoparticles (ZnONPs) are functional and inexpensive NPs that possess antimicrobial characteristics, stability, microbial selectivity, and an easy manufacturing procedure. Imidazolium is one of the quaternary ammonium compounds (QACs) frequently employed as antimicrobial materials in industrial and clinical fields. The present study successfully employed imidazolium to couple with ZnONPs to improve their antimicrobial properties. The antimicrobial activities of ZnONPs doped with imidazolium (IM@ZnONPs) compared to ZnONPs and zinc (Zn) ions against some pathogen microorganism species including Streptococcus aureus (S. aureus), Enterococcus faecalis (E. faecalis), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Candida albicans (C. albicans) were evaluated by the microdilution method. The minimum inhibitory concentration (MIC) results revealed that the antimicrobial activities of Zn ions, ZnONPs, and IM@ZnONPs were concentration-dependent. Moreover, we found that the nanoparticulate forms of Zn had considerably stronger antibacterial activities, particularly against VRE and MRSA, compared to Zn ions which failed to restrain the microbial strains at the tested microdilutions of this experiment (MIC: ≥512 µg/mL). Interestingly, the incorporation of imidazolium into ZnONPs resulted in significant inhibition of microbial growth in antimicrobial-resistant pathogens at low concentrations (MIC: 32 µg/mL) and effectively improved the monodispersity of the final coated NPs in terms of size and morphology. To sum up, IM@ZnONPs can be a favorable substitute for conventional antimicrobial agents to combat antimicrobial resistance in many fields, including pharmaceuticals, dental materials, and cosmetic products.