In order to take advantage of specific properties of sericin to develop cotton fabrics with the healthcare function, the cotton fabric modified with sericin (SMCF) was prepared by the periodate oxidation and subsequent treatment with sericin solution. The aldehyde groups in molecular chains of the oxidized cotton fabric crosslinked with the amino groups of sericin to form the chemical bond of Schiff’s base. The effects of periodate concentration, reaction temperature, sericin concentration and treatment time on the finishing process were investigated. The optimum finishing technology for cotton fabric was obtained. XPS analysis of the modified cotton fabric showed a characteristic peak of nitrogen element at 400.0–404.0 eV, which suggested that the sericin was fixed on the surface of cotton fabric through the Schiff’s base. The anti-ultraviolet property of the resulting SMCF improved. The breaking strength and whiteness of the modified fabric slightly decreased, whereas the moisture regain and wrinkle recovery angle of sericin treated fabric remarkably increased.