Panax ginseng (Korean ginseng) is renowned for its health-promoting properties, attributed to its bioactive compounds, including saponins, polyphenols, and polysaccharides, which possess both antioxidant and anti-aging activities. This study investigated the anti-aging and anti-inflammatory effects of compounds isolated from the hot water extract of fresh P. ginseng roots, evaluating their resistance to TNF-α/IFN-γ-induced skin cell damage. Among 14 compounds, ginsenoside Rf (compound 2) showed significant multi-target effects. In NHDFs, ginsenoside Rf and others effectively reduced intracellular ROS, demonstrating strong antioxidant properties. Additionally, they inhibited MMP-1 expression, a key enzyme in collagen degradation, and promoted pro-collagen Type I synthesis, countering the negative effects of TNF-α and supporting skin health. Further analysis showed that ginsenoside Rf reduced the secretion of inflammatory cytokines like IL-1β and IL-6, exhibiting anti-inflammatory effects. It also promoted the expression of crucial skin barrier proteins, including LOR, AQP3, FLG, and KRT1 in TNF-α/IFN-γ-stimulated NHEKs, enhancing skin hydration and structural integrity. These results suggest that compounds from P. ginseng roots, especially ginsenoside Rf, hold promise as skincare agents targeting skin aging and inflammation. Future research should further explore their mechanisms and optimize their applications in dermatological treatments.