Abstract: Background and Objective: Bacterial strains resistance to conventional antibiotics has gained the attention of researchers to frame a materialistic approach and to identify an agent from physical source rather than biological. Zinc oxide (ZnO) has proven antimicrobial competence but had not explored as dental aid due to its solubility and agglomeration issues. This study aimed to utilize a newer technique to formulate ZnO nanoparticles and to refurbish with zein coating in order to optimize the desired pharmacological activity. Materials and Methods: Zein based ZnO nanoparticles were synthesized using hydrothermal technique at two different pH 1.24 and 11, respectively. Both zein coated and uncoated nanoparticles were characterized for particle size, surface charge, morphology, crystallinity and even metal oxide compatibility studies. In vitro dissolution studies were performed in order to determine the effect of zein over the solubility and release of ZnO nanoparticles. Antimicrobial assay for the zein coated ZnO nanoparticles were performed on Streptococcus mutans, Staphylococcus aureus, Enterococcus faecalis and Candida albicans using both Kirby-bauer and direct kill tests. Results: The uncoated ZnO nanoparticles were in 25 nm size but aggregate, tend to increase up to 280 nm after 1 h aqueous dispersion, oppositely zein coated were 40 nm with no aggregation. Scanning electron microscopy indicated agglomerate of uncoated ZnO nanoparticles while as distinct nanospheres when zein coated. Uncoated and zein coated nanoparticles exhibited a surface charge of 28 and -24 mV at pH 1.24 and -18 and -20 mV at pH 11, respectively. X-ray crystallography indicated crystalline nature and Fourier-transform infrared spectra with no possible interaction or formation of new product. Interestingly, at pH 1.4, zein coated ZnO nanoparticles release was just 20% at 12 h in comparison to uncoated indicating prolonged release. Conclusion: The synthesized zein coated ZnO nanoparticles were found to be highly crystalline with enhanced solubility and better compatibilities. Among the four microbial strains tested, zein coated ZnO nanoparticles exhibited higher pharmacological activity against C. albicans strains in comparison to the uncoated. These experimental outcomes can indicate the potential of ZnO nanoparticles in formulating an antimicrobial dental aid.