There is a growing body of evidence that physical exercise improves neuropathic pain. However, the exact mechanisms behind exercise-induced attenuation of neuropathic pain are not fully understood. Recent studies raised one possibility that epigenetic mechanisms are involved in the pathogenesis of neuropathic pain. The present study examined whether acetylation of histone via epigenetics regulation in microglia contributes to the process of exercise-induced attenuation of neuropathic pain. Male mice received partial sciatic nerve ligation (PSL), and PSL mice were divided into PSL-control mice without exercise, low-intensity, moderate-intensity and high-intensity runner mice. Runner mice received PSL surgery after two weeks of pre-exercise acclimation, and then subjected to treadmill running from 2 days after PSL for 5 days. PSL-control mice developed remarkable mechanical allodynia and thermal hyperalgesia. In low- and moderate-intensity runner mice, behavioral hypersensitivities were attenuated, while pain symptoms of high-intensity runners were not influenced by exercise. PSL significantly increased the number of HDAC1⁺cells in the ipsilateral dorsal horn, and HDAC1-immunoreactivity was detected in CD11b⁺ microglia and GFAP⁺ astrocytes. HDAC1-expression in microglia was increased in PSL mice, while low- and moderate-intensity running exercise significantly decreased the expression of HDAC1. On the other hand, CBP-expression in microglia was decreased in PSL-control mice, while running exercise increased CBP-expression in microglia. In accordance with the changes of CBP and HDAC1, enhanced expression of acetylated histone H3K9 in microglia was detected in the runner mice. Our data indicated that low- and moderate-intensity running exercise displays beneficial effects on neuropathic pain in PSL mice, and suggested that epigenetic mechanisms that can cause hyperacetylation of chromatin histone in microglia play important roles in exercise-induced analgesia. Thus, our study provided a new insight into potential mechanisms underlying running exercise-induced attenuation of neuropathic pain.