To combat insect pests and vectors that are responsible for high losses in food and lives, insecticide discovery is of top priority. This study aimed to synthesize, characterize and investigate the insecticidal activity of 1,3,4-oxadiazole derivatives grafted on chitosan (CS) and modified polymethyl methacrylate (PMMA). 5-(pyridin-3-yl)-1,3,4-oxadiazole-2-thiol and 5-(pyridin-4-yl)-1,3,4-oxadiazole-2-thiol were respectively reacted with ethylchloroacetate and methyl-2-choloroacetoacetate. The resulted esters were grafted with CS and modified-PMMA. The products were characterized using FT-IR, 1H NMR, TGA, and XRD techniques. Four CS grafted ones were able to show good insecticidal activity against the cotton leafworm Spodoptera littoralis. Furthermore, the safety of these compounds was tested using MTT assay on a human cell line (WI-38). The results indicated that compounds 2a, 2b, 6a, and 6d are considered insecticide candidates to S. littoralis fourth-instar larvae. Cytotoxicity of 2b and 6d indicated that they are the least toxic to humans. It is concluded that both compounds may represent promising insecticide candidates. •Insecticide discovery is now of top priority.•Spodoptera littorlais is a prime candidate for pests in Africa and Europe.•Oxadiazole derivatives have insecticidal capacity against the cotton leafworm.•Compounds CS-S-oxadiazole and CS-Chloroester-S-oxadiazole are good candidates as insecticide for controlling S. littoralis.