To address trade-off and membrane-fouling challenges during the development of nanofiltration membranes, a thin-film composite membrane was prepared on the basis of interfacial polymerization regulated by adjusting the capsaicin-derived self-polymer poly N-(2-hydroxy-5-(methylthio) benzyl) acrylamide (PHMTBA) on the polysulfone substrate in this study. Through the self-polymerization of the monomer HMTBA with varied contents, microwave-assisted technology was employed to develop a variety of PHMTBAs. It was discovered that PHMTBA is involved in the interfacial polymerization process. Piperazine and PHMTBA competed for the reaction with trimesoyl chloride, resulting in a flatter and looser membrane surface. The PHMTBA-modified membrane presented a typical double-layer structure: a thicker support layer and a thinner active layer. The addition of PHMTBA to membranes improved their hydrophilicity and negative charge density. As a result, the PHMTBA-modified membrane showed dependable separation performance (water flux of 159.5 L m⁻² h⁻¹ and rejection of 99.02% for Na₂SO₄) as well as enhanced anti-fouling properties (flux recovery ratio of more than 100% with bovine serum albumin-fouling and antibacterial efficiency of 93.7% against Escherichia coli). The performance of the prepared membranes was superior to that of most other modified TFC NF membranes previously reported in the literature. This work presents the application potential of capsaicin derivatives in water treatment and desalination processes.