To discover and develop novel active molecules, in this study, a series of novel pyrethrin derivatives containing 1,3,4-oxadiazole and thioether moieties were designed and synthesized. Bioassay results revealed that some of the target compounds possessed good insecticidal activities against Plutella xylostella (P. xylostella), Vegetable aphids (V. aphids), and Empoasca vitis (E. vitis), respectively, which were even better than those of the commercial insecticidal agents chlorpyrifos, beta cypermethrin, spinosad, and azadirachtin. The results favored our rational design intention and provide a new class of small-molecule inhibitors available for the development of active insecticidal agents targeting P. xylostella, V. aphids, and E. vitis.