The Ion-Sensitive Field-Effect Transistor (ISFET) has traditionally been used to measure hydrogen ion concentration (pH) of a solution. Its performance depends mainly on its sensitivity to pH change of the electrolyte in contact with its gate. This sensitivity is usually calculated by examining the effect of pH value on the charge and potential distributions above gate insulator, which is translated into a shift in the threshold voltage. In this work, we propose a methodology to extract the sensitivity of ISFET by linking electrolyte charge and potential equations with a device simulation tool to calculate the ISFET’s drain current, thus, taking into account the underlying structure’s physical properties. Using the proposed methodology, the sensitivity of ISFET is compared for various pH values and gate-insulator thicknesses searching for the optimum conditions that give the highest sensitivity.