Five new compounds, a flavonol glycoside (1), a megastigmane (2), 2 cyclohexylethanoids (3, 4), and a phenylethanoid derivative (5), together with 15 known compounds (6–20) including flavonoid glycosides, cyclohexylethanoids, and phenolic compounds, have been isolated from Cornus sanguinea drupes. All the structures have been determined by 1D and 2D NMR spectroscopic analysis and mass spectrometry data. The antioxidant capability of the most representative isolated compounds was evaluated in the hydrogen peroxide (H2O2)-induced premature cellular senescence model of human dermal and gingival fibroblasts. Several derivatives counteracted the increase of reactive oxigen species (ROS) production in both cellular models. Among the most promising, compounds 8, 14, and 20 were able to counteract cell senescence, decreasing the expression of p21 and p53. Furthermore, compound 14
decreased the expression of inflammatory cytokines (IL-6) in both cell models and counteracted the decrease of collagen expression induced by the H2O2 in dermal human fibroblasts. These data highlight the anti-aging properties of several isolated compounds from C. sanguinea drupes, supporting its possible use in the cure of skin or periodontitis lesions.