Objective To investigate the effect and mechanism of Z-guggulsterone (Z-GS) on removing slough and promoting muscle growth in skin ulcer of diabetic rats by extracellular regulated protein kinase (ERK)/mitogen activated protein kinase (MAPK) pathway. Methods Ten of the 65 rats were selected as healthy group, and the rest were used to establish the diabetic skin ulcer model. Removing 11 rats died during modeling, 44 successful modeling rats were randomly divided into model group, Z-GS group, inhibitor+Z-GS group and positive control group (11 each). No intervention was given to the rats in healthy group, the model groups were treated with vaseline gauze to cover the wounds. Z-GS was used in Z-GS group, PD98059+Z-GS was used in inhibitor+Z-GS group, and compound sulfadiazine zinc gel was used in positive control group, the treatment lasted for 4 weeks. The changes of healing rate of skin ulcer within 4 weeks after intervention in the model groups were recorded. The changes of serum inflammatory factors were detected by ELISA. HE staining was used to observe the histological structure of skin ulcer. The microvessel density (MVD) in wound tissue was detected by immunohistochemistry. Western blotting was used to detect the expression levels of ERK/MAPK pathway related proteins in the model group, inhibitor+Z-GS group and Z-GS group. Results From model group to inhibitor+Z-GS group, Z-GS group and positive control group, the wound healing rate of rats in turn increased in a time-dependent manner (P<0.05), while the levels of serum interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α)decreased in turn (P<0.05). Compared with model group, the new skin structure was nearly complete, inflammatory cell infiltration was rare, capillary content was abundant and collagen fibers were thicker in positive control group; the epidermis was obviously thickened, and the wound coverage was thicker scab, inflammatory cell infiltration decreased, capillary content was abundant and collagen fibers were small in inhibitor+Z-GS group and Z-GS group; compared with that in positive control group, the new skin was less complete, the inflammatory cell infiltration relatively increased, and the capillary blood vessels and collagen fibers were not abundant in inhibitor+Z-GS group and Z-GS group. From model group, inhibitor+Z-GS group to Z-GS group, the expression levels of phosphorylated ERK1/2 (p-ERK1/2) and phosphorylated MAPK (p-MAPK) protein in wound tissue of rats increased in turn (P<0.05). Conclusion Z-GS may play the role of removing slough and promoting muscle growth by activating ERK/MAPK pathway in diabetic rats with skin ulcer.