A total of 22 novel stilbene derivatives containing the 1,3,4-oxadiazole moiety and trimethoxybenzene were designed and synthesized. Their chemical structures were characterized by (1)H and (13)C nuclear magnetic resonance, infrared, and high-resolution mass spectrometry. Bioassay results revealed that some of the title compounds showed potent in vivo fungicidal activities against three phytopathogenic fungi (Pseudoperonospora cubensis, Colletotrichum lagenarium, and Septoria cucurbitacearum) from cucurbits at 600 μg/mL. Notably, compounds 4b, 4d, 4i, 4k, and 4l exhibited a broad spectrum and remarkably high activities against those fungi, some of which even showed a comparable control efficacy to that of the commercial fungicides. Three-dimensional quantitative structure-activity relationship based on comparative molecular field analysis with good predictive ability (q(2) = 0.516; r(2) = 0.920) was reasonably discussed. For the first time, the present work suggested that the stilbene derivatives containing the 1,3,4-oxadiazole moiety could be developed as potential fungicides for crop protection.