While the US Food and Drug Administration has not approved the use of 3% papain gel in the United States, the authors feel this study adds to the literature regarding its use. Introduction. The aim of this study was to evaluate the effect of 3% papain gel on wounds in mice. Materials and Methods. Thirty healthy C57BL mice (25-30 g) aged 10 weeks were randomly divided into 2 groups: mice treated with 3% papain gel and mice treated with placebo gel. Skin incisions were performed with a 6-mm metallic punch with a cutting blade edge. On days 3 and 7 after creating the lesion, the mice were euthanized and lesion samples were collected. The lesion samples were processed and sectioned into 3 fragments of skin to be stained with 3 types of dye: hematoxylin and eosin, Picrosirius red, and Weigert. In addition, immunohistochemical analysis (alpha-SM actin and Ki67) followed by real-time polymerase chain reaction (PCR) protocol was performed on the samples. Results. On gross examination, the 3% papain-treated group took less time to heal the wounds compared with the control. On day 7, microscopic examination showed the 3% papain-treated group had lower numbers of inflammatory cells, increased neovascularization, and improved organization of collagen and elastic fibers. Using PCR analysis, the 3% papain-treated group showed a significant increase in transforming growth factor beta and interleukin-6 expression compared with the control (P < .05). Conclusion. Due to a reduced local inflammatory response, increased angiogenesis, and improved organization of collagen deposition, these findings demonstrate 3% papain gel can improve cutaneous wound healing in mice.