Based on the “plug-in molecular” method, a series of novel strobilurin derivatives with aryloxypyridinyl-1-ethanone oxime side chains were designed, synthesized, and screened. The biological activity experiment showed that they had an excellent fungicidal effect on plant pathogens, especially Sclerotinia sclerotiorum. Compounds 5-01 and 5-09 had significant fungicidal activity and broad fungicidal spectrum. The structure–activity relationship indicates that the cis configuration, increasing the number of pharmacophores, substitution of the 2 position of the pyridine ring, and the introduction of chlorine atom on the benzene ring were not conducive to the fungicidal activity of such compounds. The model of 3D-QSAR indicated the introduction of large electropositive groups at the 4 position of the benzene ring and the introduction of small electronegative groups at the 2 position of the benzene ring were beneficial to the fungicidal activity, and compounds 6 were designed. Compared with azoxystrobin, compound 6-02 had a more effective fungicidal effect against Sclerotinia sclerotiorum (Lib.) de Bary. Cytotoxicity test and transmission electron microscopy showed that the modification of strobilurins fungicide by the “plug-in molecular” method would not affect its toxicity and mechanism. The “plug-in molecular” method is an efficient method for screening highly active compounds, which has important guiding significance for creating new pesticide molecules.