Wound healing is a complex biological dynamic process that involves the transfer of multiple growth factors (GF) from the extracellular matrix (ECM) to fibroblasts for migration, proliferation, and wound closure. Among them, epidermal growth factor (EGF) as the most representative GF has been studied in deeply. Collagen is the most abundant ECM structural protein and has been widely used in tissue engineering for skin repair and skin remodeling. A recombinant human-like collagen (RHC) has been constructed to substitute nature collagen to improve its solubility and immunogenicity. We combined RHC and EGF to obtain a freeze-dried dressing to mimic the function of ECM for skin repair. A synergy occurred when combined EGF and RHC, that was significantly promoted the proliferation, adhesion and extension of fibroblasts (NIH/3T3) and migration of keratinocytes (HaCaT). RHC/EGF freeze-dried dressing was a loose and porous cake and redissolved quickly. RHC/EGF freeze-dried dressings significantly accelerated wound closure, re-epithelialization, orderly arrangement and deposition of collagen in the Sprague-Dawley rats with full-thickness skin defects. Further molecular mechanisms involved to cell proliferation and angiogenesis were carried out. The cell proliferation biomarkers (Ki67 and PCNA) and angiogenesis biomarkers (VEGF and CD31) were significantly up-regulated treated with RHC/EGF freeze-dried dressing. These findings demonstrated RHC/EGF freeze-dried dressing would be a potential therapeutic strategy in wound management.