A novel water-soluble sulfated derivative, kaempferol-3′-sulfonate acid sodium (KS) with the composition of [C15H9O9SNa]·2.5H2O, was synthesized and characterized by elemental analysis, IR, 1H NMR, 13C NMR, and HRMS. Its protective effects on human vascular smooth muscle cells injured by hydrogen peroxide were evaluated by CCK-8 method, flow cytometry, and Western blotting. The experimental results indicated that the KS can significantly increase cell viability and reduce apoptosis on H2O2-injured VSMCs, as well as reverse the effects of H2O2 on Bcl-2, Bad, and caspase-3 expressions. In addition, LDH leakage, MDA levels, and SOD and GSH activities were also measured with spectrophotometry. The results indicated that the KS acted as antioxidant preventing LDH leakage and MDA production, while increasing intracellular SOD and GSH activities. These findings revealed that KS might potentially serve as an effective antioxidant agent for prevention and treatment of vascular disease caused by H2O2-injured VSMCs.