Background: Ultraviolet (UV) light induces dermis destruction by modulating the expression levels of extracellular matrix-associated genes and promotes skin aging. Sirtuin 6 (SIRT6), an established anti-aging protein, regulates collagen metabolism. However, the exact mechanism of SIRT6 expression regulated in dermal fibroblasts during the skin aging process is still unknown. Objectives: We aimed to elicit the mechanism of SIRT6 expression during the skin aging process. Methods: Human dermal fibroblasts (HDFs) were cultured and total RNA was isolated. Using real-time polymerase chain reaction (Real-Time PCR) system, mRNA expression levels of α-1-type 1 collagen (COL1A1) were detected. Protein expression levels of SIRT6 were detected using western blot analysis. Results: This study revealed that microRNA-378b (miR-378b) expression was induced in UVB-exposed HDFs, and it was inversely correlated with the mRNA expression levels of COL1A1. In addition, SIRT6, a regulator of COL1A1, was directly targeted by miR-378b and its translation was inhibited. Conclusion: This study suggests that the COL1A1 mRNA expression levels are inhibited by miR-378b through interference of translation of SIRT6 mRNA. Therefore, miR-378b may associate with skin aging and collagen expression.