In this study, various types of extended gate field effect transistor (EGFET) biosensors were compared and then a model based on potential coupling between a disposable extended gate (EG) capacitor and the gate-source/drain capacitor of a nanobelt field effect transistor (NBFET) was developed and optimized for biosensor applications. Several parameters, including the dielectric thicknesses and the EG gate area coverage, the ionic strength of buffer solution, and the charge density of specific binding biomolecules, were included in the model. The potential coupling efficiency between the potential induced by surface charge on the EG and the gate voltage of the FET was analyzed and verified through pH detection. Biotin-streptavidin/avidin sensing was demonstrated with the optimized EG and NBFET. In addition, real-time measurements of the detection of botulinum neural toxin (BoNT) type-A were also performed using the EG NBFET, which could detect an extremely low concentration (20 fM) of BoNT type-A. Because the nanoelectronic field effect transistor does not need to be sacrificed after detection, the optimized EG NBFET biosensor has great potential for use in bio/chemical and point-of-care applications.