The presence of antibiotic traces in the aquatic system due to the inefficient treatment of the pharmaceutical wastewater represented threats, such as bioaccumulation and antibiotic-resistance, to the environment and human health. Accordingly, for the first time, the current work utilized the photocatalytic degradation and the adsorption approach for Levofloxacin (LEVO) in pharmaceutical wastewater using new designed nano aspects. Therefore, spherical Zinc oxide nanoparticles (ZnONP) sized 17 nm and ultrathin sheet-like structure graphene oxide nanosheets (GONS) with layer thickness ~5 nm were fabricated separately or in a combination between them then characterized via Transmission Electron Microscope (TEM), Scanning Electron Microscope (SEM), X-Ray Diffraction (XRD), Fourier Transforms Infrared Spectroscopy (FTIR), absorption spectra (UV-Vis) and Brunauer-Emmett-Teller (BET). Additionally, several parameters were investigated to evaluate the potential of the removal process, such as pH, the exposure time to UV radiation, the type and concentration of the nanoparticles (NPs) and the initial concentration of the drug using a mixed fractional factorial design. The most effective parameter for LEVO removal was the NPs type followed by the initial drug concentration. Furthermore, an RP-HPLC/UV method was developed and validated for measuring the percentage of removal for LEVO drug. The highest percentage removal for both 50 and 400 µg mL-1 LEVO was 99.2% and 99.6%, respectively, which was achieved using ZnONP/GONS combination at pH 9 ± 0.05 and UV light exposure time 120 min. In addition, the negative antibacterial activity of the treated wastewater sample confirmed the drug removal. The established protocol was successfully applied on wastewater samples collected from a pharmaceutical company that encouraged researchers to mainstream this design to be applied on other pharmaceutical wastewater drugs.