This study focuses on the fabrication of flat-sheet thin-film composite poly(piperazine-amide)-based nanofiltration membrane with enhanced both perm-selectivity and fouling resistance. Sericin was used as the co-reactant of piperazine (PIP) to form the selective skin layer through the interfacial reaction with trimesoyl chloride (TMC) on the surface of polysulfone porous support. Membranes prepared with different contents of sericin were rigorously characterized to investigate the effects of the incorporation of sericin on membrane physico-chemical and permeation properties. ATR-FTIR and EDX analyses confirmed the incorporation of sericin in the formed active layer, which was found to significantly enhance membrane water flux through enlarging membrane pore size and increasing surface hydrophilicity while maintaining Na2SO4 rejection through intensifying electrostatic repulsion effect. Membranes with both enhanced water permeability and solute selectivity could be prepared through controlling the content of sericin. For instance, by adding 0.06%(w/v) of sericin into the PIP-aqueous solution, the pure water permeability was enhanced by 36.7%, the Na2SO4 rejection was remained as high as 97.5% of the PIP-TMC membrane, and the selectivity to mixed NaCl/Na2SO4 solution was increased from 21.2 to 25.2. Moreover, the incorporation of sericin was also found to endow the membrane with improved fouling resistance to bovine serum albumin.