A novel series of HDAC inhibitors featuring a 5-(trifluoromethyl)-1,2,4-oxadiazole core and a diphenyl ether scaffold was designed and synthesized. These compounds demonstrated potent in vivo fungicidal activity against Sphaerotheca fuliginea and Puccinia sorghi . Notably, compounds IIIJ-1 to IIIJ-3 achieved 95–100% control efficacy at 25 mg/L, comparable to propiconazole. SAR studies revealed that activity was governed by the oxadiazole position and amidine substituents. Molecular docking and DFT calculations elucidated their potential binding mode to HDAC isoforms. This work identifies these compounds as promising lead structures for novel HDAC-targeting fungicides.