Abstract BACKGROUND Wheat powdery mildew is an airborne multi‐cycle disease caused by Blumeria graminis f. sp. tritici . This disease can cause severe yield reduction or total crop loss. Fluopyram is a succinate dehydrogenase inhibitor (SDHI) used for the prevention and control of gray mold, powdery mildew, and downy mildew in fruits and vegetables. RESULTS We used fluopyram to treat wheat seeds and demonstrated excellent control of powdery mildew. Fluopyram treatment did not affect wheat seed germination. After seed treatment, the residual amounts of fluopyram in harvested wheat grains and in soil were lower than the maximum residue limit (MRL, 0.07 mg kg −1 ). We explored the mechanism of action of fluopyram on wheat powdery mildew using eukaryotic reference transcriptome analysis. The differentially expressed genes (DEGs) in wheat plants treated with fluopyram were mostly enriched in the photosynthesis pathway. SPAD (soil–plant analysis development) value measurements showed a significant increase in chlorophyll content after treatment. The enzyme activity of chitinase and the relative expression levels of related genes ( Cht3 and Cht4 ) were significantly up‐regulated, indicating that the defense response of wheat was activated. CONCLUSION Fluopyram seed treatment is expected to be developed for the control of wheat powdery mildew. The research in this study will provide important theoretical basis for controlling wheat powdery mildew caused by Blumeria graminis f. sp. tritici in the field. © 2025 Society of Chemical Industry.