Abstract: In order to explore novel green fungicides, 30 new vanillin sulfate derivatives were designed and synthesized using vanillin—a natural product with promising biological activity—as the lead compound. The structures of all compounds were confirmed by ¹H NMR, ¹³C NMR, and HRMS. The inhibitory effects of the target compounds against Rhizoctonia solani, Phytophthora capsici, Valsa mali, Botryosphaeria dothidea, Botrytis cinerea, and Fusarium graminearum were evaluated using the mycelial growth rate method. The results indicated that all target compounds exhibited inhibitory activities against the tested pathogens at a concentration of 50 μg/mL. Notably, compounds 1s (O-(4-formyl-2-methoxy) phenyl-O'-(4-iodo) phenyl sulfate), 1u (O-(4-formyl-2-methoxy) phenyl-O'-(4-trifluoromethyl) phenyl sulfate), and 1x (O-(4-formyl-2-methoxy) phenyl-O'-(2-bromo-4-fluoro) phenyl sulfate) showed significant activity against V. mali, with EC₅₀ values of 1.24, 5.04, and 4.55 μg/mL, respectively. Their antifungal activity was comparable to that of the commercial control fungicide carbendazim. Compound 1s possesses advantages such as high activity, simple structure, and ease of synthesis, making it a promising lead compound for further structural optimization in the development of novel fungicides.