The polysiloxane-modified polyurethane anti-pilling finishing agent (SA-PU) was synthesized with 2,4-tolylene diisocyanate (TDI), polyester diol (PDHA), and amino-terminated siloxane (SA) as raw materials. The structure of SA-PU was characterized by Fourier transform infrared spectroscopy (FTIR). Scanning electron microscope (SEM) and energy dispersive spectrometer (EDS) showed that SA-PU had been successfully finished on the surface of the fabric. Moreover, the properties of SA-PU on the treated fabric were measured by Martindale abrasion, pilling tester, and Kawabata Evaluation System for Fabrics (KES-F). The results indicated that the anti-pilling property of polyester-cotton fabric was improved 2~3 grades after finishing. In addition, the surface properties and bending properties of polyester-cotton fabric were also improved.