Persistent postoperative pain causes influence the life quality of many patients. The Epac/PKC pathway has been indicated to regulate mechanical hyperalgesia. The present study used skin/muscle incision and retraction (SMIR) to induce postoperative pain in rats and evaluated the Epac/PKC pathway in postoperative pain. Mechanical allodynia was assessed by paw withdrawal threshold before and after incision. The levels of Epac, PKC, proinflammatory cytokines, and blood-nerve barrier-related proteins were assessed using Western blotting. We found that SMIR induced the activation of the Epac/PKC pathway, mechanical allodynia, and upregulation of Glut1, VEGF, and PGP9.5 proteins in dorsal root ganglia. Under the influence of agonists of Epac/PKC, normal rats showed mechanical allodynia and increased Glut1, VEGF, and PGP9.5 proteins. After inhibition of Epac1 in rats with SMIR, mechanical allodynia was alleviated, and proinflammatory cytokines and Glut1, VEGF, and PGP9.5 proteins were decreased. Moreover, dorsal root ganglia neurons showed abnormal proliferation under the activation of the Epac/PKC pathway. Using Captopril to protect vascular endothelial cells after SMIR had a positive effect on postoperative pain. In conclusion, SMIR regulates the persistent postoperative pain in rats by the Epac/PKC pathway.