Accumulating evidence demonstrates the beneficial effects of physical exercise on pain conditions; however, the underlying mechanisms are not understood thoroughly. The purpose of the present study was to investigate the effects of regular swimming exercise on neuroma pain and the possible roles of adipokines (leptin and adiponectin) in the pain behaviors modulated by exercise. The results showed that 5 weeks of regular swimming exercise relieved pain behaviors in a rat model of neuroma pain and normalized the dysregulation of circulating leptin and adiponectin in plasma induced by nerve injury. Moreover, regular swimming exercise reversed the altered expressions of leptin receptor and adiponectin receptor 1 in neuroma. In addition, the administration of exogenous leptin to the neuroma site dampened the effects of regular swimming exercise on neuroma pain and adiponectin administration alleviated the neuroma pain in the non-exercised neuroma rats. These findings indicate that leptin and adiponectin might be involved in mediating the beneficial effects of exercise on neuroma pain. PERSPECTIVE: Perspective: Identifying which endogenous processes are activated by specific exercise regimes would likely reveal novel therapeutic targets for the treatment of neuropathic pain. The current study suggests that adipokines might be involved in pain behaviors modulated by exercise and thus presents them as potential targets for pain management.