The nanofiltration membranes were prepared based on Poly Ether Sulfone (PES) via the phase inversion method in the study. The membranes were subsequently fabricated through interfacial polymerization between Piperazine (PIP) and Trimesoyl Chloride (TMC) monomers. Consequently, the fabricated membranes were modified using Bismuth Oxide (Bi2O3) nanoparticles. Bi2O3 nanoparticles were dispersed in PIP aqueous solution (Nano Bi2O3-TFCaq) and in TMC organic solution (Nano Bi2O3-TFCorg) by two different procedures to investigate the effect of nanoparticles and the manufacturing process on membrane properties. The prepared membranes were characterized via Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) analysis, atomic force microscopy (AFM), tensile strength, and zeta potential analysis. The tests were performed to check the surface structure, chemical composition, and hydrophilicity of the modified membrane. Also, the salt and BSA rejection rate of the membranes were investigated. Besides, both modified membranes were used to remove Hydrochlorothiazide (HCTZ) drug as the target pollutant. Eventually, it was concluded that the novel Nano Bi2O3-TFC membranes could be so useful in wastewater treatment.