The impaired wound healing in diabetes is a central concern of healthcare worldwide. However, current treatments often fail due to the complexity of diabetic wounds, and thus, emerging therapeutic approaches are needed. Macrophages, a prominent immune cell in the wound, play key roles in tissue repair and regeneration. Recent evidence has demonstrated that macrophages in diabetic wounds maintain a persistent proinflammatory phenotype that causes the failure of healing. Therefore, modulation of macrophages provides great promise for wound healing in diabetic patients. In this study, the potential of paeoniflorin (PF, a chemical compound derived from the herb ) for the transition of macrophages from M1 (proinflammatory phenotype) to M2 (anti-inflammatory/prohealing phenotype) was confirmed using and experimental approaches. A hydrogel based on high molecular weight hyaluronic acid (HA) was developed for local administration of PF in experimental diabetic mice with a full-thickness wound. The resultant formulation (HA-PF) was able to significantly promote cutaneous healing as compared to INTRASITE Gel (a commercial hydrogel wound dressing). This outcome was accompanied by the amelioration of inflammation, the improvement of angiogenesis, and re-epithelialization, and the deposition of collagen. Our study indicates the significant potential of HA-PF for clinical translation in diabetic wound healing.