Human skin aging has internal and external factors, both of which are characterized by TNF-α overproduction. Therefore, we aimed to identify a natural product that suppresses the damage that occurs in cutaneous dermal fibroblasts exposed to TNF-α. The protective effects of the indole alkaloid -glycoside, ginkgoside B dimethyl ester (GBDE), isolated from ginkgo fruit ( fruit) were evaluated in TNF-α stimulated human dermal fibroblasts (HDFs). GBDE inhibited TNF-α-induced MMP-1 expression to 2.2 ± 0.1-fold ( < 0.01) and reversed the decrease in collagen levels to 0.4 ± 0.00-fold ( < 0.01) at 50 μM. The effect of GBDE was due to the suppression of the phospolylaton of MAPKs (ERK, 0.47 ± 0.05; JNK, 1.21 ± 0.07; p38, 0.77 ± 0.07-folds, < 0.001) and Akt (0.14 ± 0.03-fold, < 0.001) compared to the TNF-α group. GBDE also reduced the expression of COX-2 to 2.06 ± 0.12-fold ( < 0.001) and increased the expression of HO-1 to 10.64 ± 0.2-fold ( < 0.001). In addition, GBDE inhibited the expression of the pro-inflammatory cytokines (IL-8, 2.2 ± 0.0; IL-1β, 1.6 ± 0.0; IL-6, 2.0 ± 0.10-folds, < 0.05). These results provide experimental evidence that GBDE can protect against skin damage, including aging.