Abstract: The paper presents modeling and simulation of ion-sensitive field-effect transistor (ISFET)-based pH sensor with temperature-dependent behavioral macromodel and proposes to compensate the temperature drift in the sensor using intelligent machine learning (ML) models. The macromodel is built using SPICE by introducing electrochemical parameters in a metal-oxide-semiconductor field-effect transistor (MOSFET) model to simulate ISFET characteristics. We account for the temperature dependence of electrochemical and semiconductor parameters in our macromodel to increase its robustness. The macromodel is then exported as a subcircuit element, which is used to design the readout interface circuit. A simple constant-voltage, constant-current (CVCC) topology is utilized to generate the data for temperature drift in ISFET pH sensor, which is used to train and test state-of-the-art ML-based regression models in order to compensate the drift behavior. The experimental results demonstrate that the random forest (RF) technique achieves the best performance with very high correlation and low error rate. Corresponding curves for output signal using the trained models show highly temperature-independent characteristics when tested for pH 2, 4, 7, 10, and 12, and we obtained a root mean squared error (RMS) variation of ΔpH ≤ 0.024 over a temperature range of 15◦C to 55◦C in comparison with ΔpH ≤ 1.346 for uncompensated output signal. This work establishes the framework for integration of ML techniques for drift compensation of ISFET chemical sensor to improve its performance.