A global upsurge in antibiotic resistance has led to research in metal-based antimicrobial therapy. Nonetheless, the clinical translation of metal oxides is often hampered by their poor aqueous solubility. This work unravels the surfactant-free synthesis of a water-soluble PEGylated nanographene oxide/zinc-doped copper oxide complex (NGO-PEG-Zn-CuO) with superior antibacterial activity. We uncover its mechanism of bacterial cell death over E. coli and S. aureus associated with oxidative stress and high production of reactive oxygen species (ROS) compared to NGO-ZnCuO, ZnCuO and NGO-PEG. A simple, one-step sonochemical technique is employed to deposit the Zn-CuO nanoparticles (NPs) on NGO-PEG. This complex demonstrates excellent aqueous solubility in different physiological solutions, including serum. Moreover, it exhibits excellent stability in water for a period of more than two months with almost no cytotoxicity effect on HeLa cells. Taken together, these results display the superior potency of the NGO-PEG-ZnCuO complex as a soluble and non-toxic compound with enhanced antibacterial properties.