Background: The use of epidural steroid injection in spinal stenosis pain management has expanded greatly. Calcitonin is also effective in relieving neuropathic pain in spinal canal stenosis through the mechanisms of arterial dilation, anti-inflammation, anti-edema, and rises in beta endorphin levels. The current study was designed to evaluate the effect of mesotherapy with calcitonin compared with epidural steroid injection for pain relief and functional improvement in patients with lumbosacral canal stenosis. Methods: A total of 39 patients comparable in age and gender with signs and symptoms of lumbosacral canal stenosis participated in this randomized control trial. Group A comprised patients receiving mesotherapy of 100 IU Calcitonin+Marcaine 0.5% (4 mL) in three repeated injections in the lumbosacral area; group B received a single caudal epidural injection of Marcaine 0.5% (4 mL)+80 mg methyl prednisolone (2 mL) under the guide of a fluoroscope. Patients were evaluated before and 4 and 8 weeks after intervention using the visual analog scale (VAS), Oswestry Disability Index (ODI), Quebec back pain disability scale (QBPD), and Ronald-Morris Disability Questionnaire (RMDQ). Results: Based on the VAS, ODI, QBPD, and RMDQ scales, a significant improvement in pain and functional disability was observed in both groups 4 and 8 weeks after intervention (P0.05). Conclusion: Mesotherapy with calcitonin Marcaine is just as effective as caudal epidural steroid injection; considering its advantages, mesotherapy can be a proper alternative method for managing pain and functional impairment in patients with lumbosacral canal stenosis.