Cathepsins are involved in regulatory mechanisms in human skin, but their role in photoaged skin remains unknown. This study investigates the role of cathepsin B, D, K, and G in skin photoaging in vivo and in vitro. Cathepsin-induced changes in skin as a result of chronic UV irradiation were detected by immunohistochemistry methods. Protein cathepsin expressions in UVA-induced premature senescence in fibroblasts in vitro were detected by Western blot technique. Cathepsin mRNA expression in photoaged skin and fibroblasts was detected by real-time reverse transcription-polymerase chain reaction. Immunohistochemistry and Western blot show lower protein expression of cathepsin B, D, and K in photoaged skin and fibroblasts, while cathepsin G was higher. The mRNA expression of cathepsin B, D, and K of the photoaged skin in vivo decreased to 20 ± 0.5, 25 ± 1.6 and 22 ± 0.8%, while cathepsin G mRNA increased to 2.24 ± 0.09 times that of control. In photoaged fibroblasts, cathepsin B, D, and K mRNA was downregulated to 64 ± 2.9, 24 ± 2.1 and 9 ± 0.5% while cathepsin G mRNA was upregulated to 1.42 ± 0.06 times that of control fibroblasts. These experiments suggest that cathepsin B, D, K, and G may act as biomarkers in photoaged human skin.