Tourniquet, as a life‐saving device, is widely used to stop extremity hemorrhage in civilian medicine and on the battlefield. However, tourniquet use and subsequent release can induce a long‐term increase in pain sensitivity called complex regional pain syndrome. Complex regional pain syndrome is a form of chronic pain triggered by inflammation and nerve dysfunction, with a great resistance to different treatments for relieving pain. Increasing evidence showed a pivotal role of neuroinflammation in the formation of hyperalgesia and allodynia. In our study, we investigated the therapeutic effects of masitinib, an anti‐neuroinflammatory drug, on ischemia‐reperfusion (IR) increased pain sensitivity in a mouse model of tourniquet‐induced hindpaw IR. Unilateral hindpaw of C57/BL6 mice were subjected to 3 hours of ischemia by placing a rubber band at ankle joint and followed 4 weeks of reperfusion. Masitinib treatment (28 mg/kg/day, i.p.) began on the day of IR induction and last for 4 weeks. Tourniquet‐induced IR caused nerve damage in the skin and abolished the paw sensation to 2 g of mechanical stimulation before the 3rd day of reperfusion. In the mice with tourniquet‐induced IR, mechanical allodynia appeared at day 7 (0.54 ± 0.10 g, compared to 0.83 g ± 0.10 in sham mice; p<0.05), reached to the maximum reaction at 2 weeks (0.19 g ± 0.04 g), and lasted 4 weeks. In the mice with masitinib plus tourniquet‐induced IR, 33% (4/12) of mice at day 1 and 40% (6/15) of mice at day 3 responded to 2 g of stimulation. Treatment with masitinib significantly alleviated IR‐induced mechanical allodynia from 2 weeks to 4 weeks. Additionally, paw thickness, a marker for hindpaw edema, was observed. Treatment with masitinib also attenuated IR‐induced expansion of the hindpaw. Our data provide the evidence that treatment with masitinib effectively alleviates complex regional pain syndrome in tourniquet‐induced hindpaw IR.