Threshold switching memristors exhibit significant potential for developing artificial nociceptors as their working principles and electrical characteristics closely mimic biological nociceptors. However, the development of high-performance artificial nociceptors is hindered by the randomness of conductive filament (CF) formation/rupture, caused by low-quality resistive switching (RS) films and complex, and uncontrollable RS mechanisms. Organic small-molecule materials are favored in electronic devices for their designability, low cost, easy synthesis, and high stability. In this study, we meticulously designed two D-π-A-π-D structured molecules, designated as TZ-1 and TZ-2, to serve as the RS layer in artificial nociceptors. By precisely modulating the electron-donating ability of the donor groups in these molecules, some key electrical properties of the memristor, such as the low SET voltage (0.42 V) and variation (0.055), high current ON/OFF ratio (˜10-6) and nanosecond level switching time (60 ns), can be successfully optimized. Moreover, a spectroelectrochemistry strategy was first employed to investigate the RS mechanism at the molecular level, elucidating the critical role of molecular design in modulating the device’s working principles and electrical characteristics. The optimized memristor is capable of accurately emulating the four key behaviors of nociceptors. This achievement not only advances the application of organic materials in neuromorphic devices but also opens new possibilities for the specialized customization of nociceptors.