To find novel and efficient nematicides, 28 2-cyanoacrylate (amide) derivatives were designed and synthesized. The structures of all target compounds were confirmed by ¹H NMR, ¹³C NMR, and high-resolution mass spectra (HRMS). The configuration of ethyl (E)-3-(4-chlorophenyl)-2-cyanoacrylate (3f) was confirmed by X-ray single crystal diffraction. The results of nematicidal activities test showed that all the target compounds had certain nematicidal activities against Meloidogyne incognita, Aphelenchoides besseyi, and Ditylenchus destructor (second-stage juveniles) after 72 h of treatment at 100 mg/L. Among them, the LC₅₀s of ethyl (E)-2-cyano-3-(4-fluorophenyl)acrylate (3i) and ethyl (E)-2-cyano-3-(furan-2-yl)- acrylate (3n) against Meloidogyne incognita for 72 h were 24.58 and 32.13 mg/L, respectively. The LC₅₀s of ethyl (E)-3-(4-(2- ((3-chloro-5-(trifluoromethyl)pyridin-2-yl)oxy)ethoxy)phenyl)-2-cyanoacrylate (17a) against A. besseyi and D. destructor were 31.97 and 38.26 mg/L, respectively, which were significantly better than that of the control agent Tioxazafen (48.95 and 74.95 mg/L). In addition, compound 3i could significantly promote the production of reactive oxygen species (ROS) and the accumulation of lipofuscin and lipid in M. incognita, which indicated that compound 3i might promote oxidative stress of M. incognita and eventually lead to the death of nematodes. Compound 3i can be used as a lead compound to develop novel nematicides.