Abstract: Objective: To investigate the therapeutic effect of L-Arginine on ultraviolet-induced skin photoaging in mice and its potential molecular mechanism. Methods: C57BL/6J mice were irradiated with UVB and UVA to successfully establish a skin photoaging model. Meanwhile, the mice were intervened with oral and transdermal administration. Subsequently, the indicators related to skin function and oxidative stress in the serum of each group of mice were measured. Hematoxylin-eosin (HE), Masson, and toluidine blue (TB) staining were used to observe the pathological changes in skin structure. Western blot and immunofluorescence were employed to detect the expressions of aquaporin 3 (AQP3) and filaggrin (FLG). Results: Following oral or transdermal administration of high-dose L-arginine, we detected significant increases in the contents of collagen I, hydroxyproline, hyaluronic acid, and ceramide in the sera of mice (P<0.05). Furthermore, we detected the enhanced activities of total superoxide dismutase and catalase (P<0.05), whereas there were significant reductions in the levels of malondialdehyde (MDA) (P<0.05), thereby indicating a clear enhancement of the antioxidant capacities of mice. Concurrently, the pathological manifestations of photoaging in skin tissue were markedly alleviated, and we detected the up-regulated expression of AQP3 and FLG proteins (P<0.05). Conclusion: By enhancing antioxidant capacity, promoting skin tissue repair, and regulating the expression of key proteins, L-arginine can contribute to an effective alleviation of photoaging damage, thereby providing a scientific basis and diverse options for the development of functional foods, functional cosmetics, and drugs.