Aim: ASM, which hydrolyzes sphingomyelin into ceramide, is recognized as a therapeutic target for UV-induced skin damage. Direct inhibitors for this enzyme are rare. Here we synthesized several series of 1,3,6,7-tetrahydroxy-xanthone derivatives as novel ASM inhibitors. Results: Several compounds were more potent than the lead compound, among which 5b was found competitively inhibiting the enzyme and dose-dependently reducing ceramide generation. Furthermore, 5b and 5c showed excellent protective effect to skin keratinocytes against UV. Quantitative structure–activity relationship investigation revealed detail relationships between molecular structure and biological activity. Insight into the binding mode was precisely illuminated by molecule docking. Conclusion: This work would provide fresh ideas and strong supports for further development of ASM inhibitors and drug candidates for skin damage.