In the manufacturing process of the microfiber synthetic leather, various types of filling agents were selected to fill the microfiber synthetic leather base to improve the sanitary properties, in which a zirconium tanning agent was used commonly. In this study, the softness, moisture absorption, water vapor permeability and mechanical properties of the base were used as indexes, and the type and dosage of the filling agent were optimized. The results indicated that the sanitary properties of the base treated by the filling agent were improved generally compared with that of the blank base. Among them, the moisture absorption increased by 28–45%, the water vapor permeability increased by 50–56% and the mechanical properties were significantly improved. The bases before and after being filled were characterized by Fourier infrared spectroscopy, the water contact angle, atomic force microscopy, scanning electron microscopy and the specific surface area. The results showed that the filling agent’s cross-linking effect on the base fiber led to the active group content and wettability of the base increasing, the fiber surface structure changing obviously and the fiber gap becoming larger with looser dispersion. Moreover, the specific surface area of the base increased.