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<i>Fusarium</i> fungi are the cause of an array of devastating diseases affecting yield losses and accumulating mycotoxins. Fungicides can be exploited against <i>Fusarium</i> and deoxynivalenol (DON) production. However, <i>Fusarium</i> resistance to common chemicals has become a therapeutic challenge worldwide, which indicates that new control agents carrying different mechanisms of action are desperately needed. Here, we found that a nonantibiotic drug, ethylenediaminetetraacetic acid disodium salt (EDTANa₂), exhibited various antifungal activities against <i>Fusarium</i> species and DON biosynthesis. The infection of wheat seeding caused by <i>F. graminearum</i> was suppressed over 90% at 4 mM EDTANa₂. A similar control effect was observed in field tests. Mycotoxin production assays showed DON production was significantly inhibited, 47% lower than the control, by 0.4 mM EDTANa₂. In vitro experiments revealed a timely inhibition of H₂O₂ production as quickly as 4 h after amending cultures with EDTANa₂ and the expression of several <i>TRI</i> genes significantly decreased. Chitin synthases of <i>Fusarium</i> were Mn²⁺-containing enzymes that were strongly inhibited by Mn²⁺ deficiency. EDTANa₂ inhibited chitin synthesis and destroyed the cell wall and cytomembrane integrity of <i>Fusarium</i>, mainly via the chelation of Mn²⁺ by EDTANa₂, and thus led to Mn deficiency in <i>Fusarium</i> cells. Taken together, these findings uncover the potential of EDTANa₂ as a fungicide candidate to manage Fusarium head blight (FHB) and DON in agricultural production.