Objective To explore the protective effect of external use of isoflavone cream on ultraviolet radiation induced skin injuries of mice and its mechanisms. Methods A total of 48 male ICR mice were randomly assigned to vehicle (control), ultraviolet radiation (UV), 2% isoflavone+UV and 3% isoflavone+UV groups, with 12 mice in each group, and the naked skin of mice in the four groups were treated with sesame oil (15 min), sesame oil (15 min) in combined UV (first radiation with 1.55 J/cm² long-wave ultraviolet[UVA] for 18 min, and then with 0.95 J/cm² middle-wave ultraviolet[UVB] for 11 min), 2% isoflavone (15 min) in combined UV and 3% isoflavone (15 min) in combined UV, respectively. After radiation for 7 days, the UV-exposed skins were obtained to observe the morphological and histological changes using H-E staining. The contents of interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) in the skins were determined using ELISA or corresponding kits. Results (1) UV irradiation caused erythema and crusting in skin, and inflammatory cell infiltration in the dermis and fractured elastic fiber were observed microscopically. Isoflavone pretreatment effectively ameliorated these damages in mice skin. (2) Compared with the control group, contents of IL-1β, IL-6 and TNF-α in the UV group were significantly increased (P<0.05); however, the contents of IL-1β, IL-6 and TNF-α were significantly reversed by isoflavone pretreatment (P<0.05, P<0.01). (3) Compared with the control group, the skin MDA content in the UV group was significantly increased (P<0.05), SOD and CAT contents were significantly decreased (P<0.05); however, the isoflavone pretreatment significantly reversed the alterations of MDA, SOD and CAT (P<0.05, P<0.01). Conclusion Isoflavone exerts protective effects against the ultraviolet induced skin damage in mice through alleviating lipid peroxidation, oxidative stress and inflammatory response.