In this study, a novel amphiphilic comb copolymer P(poly(ethylene glycol) (PEG)-r-poly(dimethylsiloxane) (PDMS)) with mixed hydrophilic and low surface energy side chains was synthesized by the free radical polymerization method. The microstructure of the synthesized amphiphilic copolymers was characterized by Fourier transform infrared (FTIR) and the nuclear magnetic resonance proton spectra (H-1 NMR). The copolymers were blended with poly(ether sulfone) (PES) to fabricate low-fouling ultrafiltration membranes through nonsolvent induced phase separation (NIPS). The surface distribution of the hydrophilic PEG segments and hydrophobic PDMS segments on the membranes via surface segregation during the NIPS process was confirmed by the X-ray photoelectron spectroscopy (XPS), the wetting property, and the surface energy measurements. The multidefense mechanisms from fouling resistant to fouling release for the membranes modified by amphiphilic copolymers P(PEG-r-PDMS) were investigated with bovine serum albumin (BSA) aqueous solution as a model foulant. The antifouling properties of the modified membrane, especially for membrane PES/P(PEG-r-PDMS)similar to 31.3% (M-4), was effectively improved in comparation with pure PES membrane (M-0). The flux decline rate of the membrane M-4 was as low as 15.6%, and the flux recover ratio was up to 96.6%. The modified membrane also possessed stable and durable antifouling properties after three cycles of BSA filtration and chemical washing. It is promising that the present study can offer an effective approach to construct a low fouling membrane in the application of wastewater treatment and water purification.