Overexpression of cyclooxygenase-2 (COX-2) leads to prostanoid formation in skin tissue, disturbs the balance between proliferation and apoptosis, and subsequently promotes tumorigenesis. In this work, amuresin G showed protection effects on JB6 C141 mouse epidermal cells exposed to UVA, which induces COX-2 protein expression and prostaglandin E2 production in an energy-dependent manner. These overexpressions were significantly decreased by amurensin G. Additionally, the increased COX-2 gene transcription in response to UVA was preceded by activation of the transcription factors nuclear factor-KB (NF-KB), cAMP response element-binding protein (CREB), CCAA T/enhancer-binding proteins alpha and beta (C/EBPalpha and C/EBPbeta) and c-Jun/activator protein-I (AP-I). Amurensin G treatment abolished the activation of NF-KB, CREB, and C/EBP by UV A irradiation. These results suggest that amurensin G inhibits UV A-induced COX-2 expression in JB6 C141 cells.