Although the electrospinning technique has been devoted to promoting therapeutic purposes as a drug carrier, however, there are still many fundamental problems in this area. This work focuses on a comparison of various diameter polyethersulfone (PES) electrospun ultrafine fibers as antimicrobial materials. The fibrous morphology, antimicrobial agent distribution, thermally property, and biocompatibility evaluation of PES-based ultrafine fibers were systematically investigated. The results demonstrated that the PES-based ultrafine fibers were suitable as antimicrobial material. Furthermore, the drug release behavior and mechanism were studied through total immersion. The release mechanism was confirmed to Fickian diffusion. It was revealed that the drug max release amount (71.5%) and release rate (7.71) are the highest for the smallest diameter ultrafine fibers. Meanwhile, the antimicrobial activity of PES ultrafine fibers is also inversely correlated with the diameter of fiber. The electrospun PES fibers would control their release behavior through the diameter and have a potential application in the wound dressings, such as chronic osteomyelitis and exposure injury.