Nanotechnology offers exciting prospects against infectious agents, particularly multidrug resistance bacteria (MDR), which is the roaring concern of this era. Zinc oxide nanoparticles (ZnO-Nps) efficiently deliver therapeutic agents into living systems due to their biocompatibility and bioactivity, which make them highly effective against infectious pathogens. The present investigation was designed to investigate the impact of the ZnO-Nps in combination with the Piperacillin-Tazobactam (TZP) drug against MDR. TZP are beta-lactam antibiotics highly effective against Gram-positive and Gram-negative bacteria such as Pseudomonas aeruginosa, and are recommended for the empirical treatment of Febrile neutropenia (FN) associated with chemotherapy treatment. For this study, three different-sized ZnONp combinations were used. The extended-spectrum beta-lactamase (ESBLs) producing Escheria coli and MDR P. aeruginosa strain sensitivity profiling towards different combinations of ZnO-Nps and Piperacillin-Tazobactam were measured. The synthesized Zno-Nps w ere d esignated a s Z n-1, Z n- 2, and Zn-3 based on their sizes, and were made in different combinations with the commercially available drug TZP (ZnO-Nps+ Drug) against MDR E.coli and P. aeruginosa. There was no synergistic effect observed against growth inhibition of E.coli. The combined dose of Zn-1 and TZP showed better antibacterial efficacy even as compared to the pure drug against P. aeruginosa. The study revealed that the dosage and biological activity of drugs used to treat fatal human diseases like cancer can be decreased while their efficacy can be boosted by using ZnO nanoparticles as powerful drug delivery systems.