Since ancient times, bees and their products have been traditionally used in the treatment of many diseases, but the synergistic effects of bee products such as royal jelly (RJ) and melittin in the treatment of skin damage are an important issue due to its availability and cheapness. In this study, a 5 mm diameter wound was created by punching the skin on the back of the neck in NMARI male mice. Wounds were treated orally and topically with different doses of RJ and melittin and their combination for 9 days. The diameter of the wounds was measured and recorded daily, and on the 10th day, the mice were anesthetized and their skin tissue samples were taken for histological examinations and hydroxyproline measurement. Histopathological sections were evaluated for the presence of fibroblasts, new blood vessels, epithelial tissue formation, collagen synthesis, presence of inflammatory cells. Synergistic effects of oral treatment with RJ (50 mg/kg) and melittin (3x10− 5 mg/kg) and combined topical treatment of RJ (2.5%) and melittin (0.5x10− 4%) caused a significant reduction in the diameter of the skin wound compared to a single dose of them. The findings of biochemical studies showed a significant increase of hydroxyproline level in the wound tissue in the group treated with RJ and melittin topically and orally compared to the control group. The synergistic effect of RJ and melittin in collagen synthesis in the skin of could confirm the use of these materials in the traditional and modern medicine for skin treatments.