In the light of promising potency of selenium nanoparticles in biomedical applications, this is the first study to report the synergistic antibacterial activity of these nanoparticles and lysozyme. The nanohybrid system was prepared with various concentrations of each component. Resistance of Escherichia coli and Staphylococcus aureus was compared in the presence of individual Nano and Bio counterparts as well as the nanohybrid system. Upon interaction of SeNPs with Lysozyme, the nanohybrid system efficiently enhanced the antibacterial activity compared to the protein. Therefore, SeNPs play an important role in inhibition of bacterial growth at very low concentrations of protein; whereas very high amount of the protein is required to inhibit bacterial growth individually. On the other hand, lysozyme has also played a vital role in antibacterial property of SeNPs, inducing 100% inhibition at very low concentration of each component. Hence, presence of both nano and bio counterparts induced vital interplay in the Nanohybrid system. The aged samples also presented good stability of SeNPs both as the intact and complex form. Results of this effort highlight design of nanohybrid systems with synergistic antibacterial properties to overcome the emerging antibiotic resistance as well as to define fruitful applications in biomedicine and food safety.