There have been developments in the optimization of polyether sulfone (PES) membranes, to provide antifouling and mechanically stable surfaces which are vital to water purification applications. There is a variety of approaches to prepare nanocomposite PES membranes. However, an optimized condition for making such membranes is in high demand. Using experimental design and statistical analysis (one-half fractional factorial design), this study investigates the effect of different parameters featured in the fabrication of membranes, as well as on the performance of a nanocomposite PES/TiO2 membrane. The optimized parameters obtained in this study are: exposure time of 60 s, immersion time above 10 h, glycerol time of 4 h, and a nonsolvent volumetric ratio (isopropanol/water) of 30/70 for PES and dimethylacetamide (PES-DMAc) membrane and 70/30 for PES and N-methyl-2-pyrrolidone (PES-NMP) membrane. A comparison of the contributory factors for different templating agents along with a nanocomposite membrane control, revealed that F127 triblock copolymer resulted in an excellent antifouling membrane with a higher bovine serum albumin rejection and flux recovery of 83.33%.