Equisetum hyemale extract promotes wound healing in diabetic rats, but its cytotoxicity limits its use. This study aimed to encapsulate the extract in collagen–polyurethane–dextran semi-interpenetrating network hydrogels containing 20–30 wt% dextran and 20–40 wt% extract. The physicochemical properties, in vitro biological responses, and wound-healing performance of the hydrogels were subsequently evaluated. The hydrogels exhibited crosslinking degrees of 65–80%, swelling capacities of 2800–3100%, predominantly elastic behavior, and structural integrity for up to 30 days under hydrolytic and proteolytic conditions. The D20C20 formulation (20% dextran and 20% extract) showed the greatest polyphenol permeation (940 µg/mL after 120 h) and permeability coefficient (Kp = 9.9 × 10⁻³ cm/h). Cell viability varied depending on the formulation, cell type, and exposure time. Macrophages and mononuclear cells exhibited transient increases in the MTT-derived viability signal after 24 h, followed by decreases after 72 h. However, fibroblast viability remained consistent across formulations. Most formulations increased IL-10 and reduced MCP-1 in lipopolysaccharide-stimulated macrophages after 72 h. No hemolysis or dermal irritation occurred under the tested conditions. In diabetic rats, D20C20 achieved complete wound closure by day 17. The regenerated tissue exhibited a more organized collagen arrangement. These findings support further investigation of D20C20 as a potential wound-healing material.