BACKGROUND: Ultraviolet B (UVB) irradiation can damage skin tissue. Diabetes aggravates skin lesions. Fibroblast growth factor 21 (FGF21) is significantly involved in exerting protective effects and facilitating tissue repair. Therefore, this study aimed to investigate the impact of recombinant human FGF21 (rhFGF21) on diabetic skin affected by UVB damage. METHODS: UVB irradiation (270 mJ/cm RESULTS: Our findings indicated that the skin of diabetic mice was more severely damaged by UVB irradiation, and rhFGF21 alleviated this damage. RhFGF21 inhibited apoptosis and inflammatory responses in the skin tissues of diabetic mice. These changes were primarily reflected in increase of the sirtuin 1 (SIRT1) level in epidermal cells and peritoneal macrophages of mice. Moreover, rhFGF21 not only increased the survival rate of HaCaT cells but also decreased the generation of pro-inflammatory cytokines in MPMs. Notably, SIRT1 inhibitor (EX527) was capable of reversing these effects. CONCLUSIONS: RhFGF21 attenuates UVB-induced damage to the skin of diabetic mice, predominantly by suppressing epidermal cell apoptosis and macrophage-mediated inflammatory responses via the SIRT signaling pathway.