As a typical pH sensitive polymer with biocompatibility, hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a promising material for application in controlled drug release. In this paper, HPMCAS micro-nanofibers were prepared through electrospinning. The optimum condition was obtained by researching the effective of the parameters such as solution concentration, applied voltage, distance and ratio of mixed solvent on fiber morphology and diameter. Through an orthogonal and a single factor experiment, the optimum parameters were determined as a polymer concentration of 12 wt %, a voltage of 20 kV, a collector distance of 20 cm and a solvent ratio (CH3OH/DCM) of 4/6. As a result, the average diameter of fibers is 363m and with good uniformity and smooth morphology. The results will provide theoretical and experimental basis for using HPMCAS nanofibers as intelligent ph-controlled drug sustained-release/controlled-release materials.