(1)Background: Inflammation plays a key role in spinal cord injury (SCI), where excessive inflammatory responses exacerbate neural damage and hinder regeneration. Modulating macrophage polarization, particularly through the sustained release of IL-10 to promote the anti-inflammatory M2 phenotype, represents a promising strategy to mitigate inflammation. In this study we developed a Hyaluronic Acid Methacryloyl (HAMA) hydrogel capable of sustained IL-10 release to regulate macrophage polarization and explore its therapeutic potential. (2)Methods: A photo-curable HAMA hydrogel was synthesized via methacrylation and designed for the sustained release of IL-10. The structural and functional properties were characterized using NMR and FT-IR. In vitro assays, including immunofluorescence, flow cytometry, and Western blotting, were performed to evaluate IL-10's effect on macrophage polarization. The anti-inflammatory and reparative effects of the hydrogel were further validated in a rat SCI. (3)Results: The HAMA hydrogel with sustained IL-10 release demonstrated excellent biocompatibility. It significantly promoted macrophage polarization to the anti-inflammatory M2 phenotype by increasing the expression of CD206. In vivo studies demonstrated that the group treated by HAMA with IL-10 exhibited recovery of sensory and motor functions, along with improvement of the inflammatory microenvironment at the site of injury. (4)Conclusion: The HAMA hydrogel with sustained IL-10 release effectively alleviates inflammation, enhances motor function after SCI, and serves as a promising immunomodulatory platform. This novel approach presents considerable potential for improving neural regeneration.