Madecassoside (MD) and rosmarinic acid (RA) are well-known compounds with wound healing and antiaging effects. We demonstrated the synergistic protective activity of the MD–RA combination in Hs68 cells against ultraviolet B (UVB)-induced photoaging. The cell viabilities of MD, RA, and MD–RA combinations at various ratios (9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, and 1:9, v/v) were measured to compare their protective effects against UVB radiation. The synergistic interaction between MD and RA was confirmed using a combination index. The strongest effect of the MD–RA combination was observed at a ratio of 3:7. The combination of MD–RA 3:7 exerted a synergistic effect against UVB-induced changes in cell viability, as well as superoxide dismutase activity, reactive oxygen species, glutathione, catalase activity, and malondialdehyde levels. Moreover, the inhibitory effect of the MD–RA combination (3:7) on matrix metalloproteinases and total collagen production was higher than that of MD or RA alone. These results demonstrated that the MD–RA combination (3:7) generated a strong synergistic effect against UVB-induced photoaging in Hs68 cells. Overall, our results provide scientific evidence to support the development of a new combination therapy for skin protection against UVB-induced photoaging through the synergistic interaction between MD and RA. These natural compounds are promising options for antiaging and skin protection in the cosmetic and pharmaceutical industries.
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