Objective To investigate the protective effect of marine traditional Chinese medicine coral calcium hydride on skin extravasation ulcer induced by epirubicin in mice, so as to provide basis for the clinical application of coral calcium hydride. Methods The mouse skin exosmotic ulcer model created by epirubicin was established. Then the mice were divided into control group (treated with routine treatment and normal saline irrigation) and experimental group (treated with routine treatment and 0.375 g/cm² coral calcium hydride in the early, middle, and late of the day, respectively). The area, degree, and healing time of exosmotic ulcer of model animals in the 2 groups were observed and recorded. After continuous treatment for 15 d, the ulcer tissue was resected and the pathomorphological changes were observed by hematoxylin-eosin (H-E) staining. The expression of Ki-67, oxidative stress-related indexes heme oxygenase 1 (HO-1), nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), inducible nitric oxide synthase 2 (iNOS2), and superoxide dismutase 1 (SOD1) in the skin and subcutaneous tissue was detected by immunohistochemistry. Results The incidence of exosmotic ulcer was 100.0% (5/5) in the control group and 60.0% (3/5) in the experimental group. The ulcer area of the experimental group was significantly less than that of the control group (P＜0.05), and the ulcer healing speed was significantly faster than that of the control group. H-E staining showed that the subcutaneous connective tissue was disordered, with hair follicle dilated and squamous epithelium thickened in the control group, while the subcutaneous tissue in the experimental group was slightly disordered, with dilated hair follicle rarely seen and thickened squamous epithelium. Immunohistochemistry showed that the expression of Ki-67 in subcutaneous tissue of the experimental group was higher than that of the control group, the expression of iNOS2 and NOX2 in the control group was significantly higher than that of the experimental group (bothP＜0.05), and the expression of HO-1 and SOD1 in the control group was significantly lower than that of the experimental group (both P＜0.05). Conclusion Marine traditional Chinese medicine coral calcium hydride has a good protective effect on skin ulcer caused by epirubicin extravasation.