The development of ion-sensitive field-effect transistor (ISFET) sensors based on silicon nanowires (SiNW) has recently seen significant progress, due to their many advantages such as compact size, low cost, robustness and real-time portability. However, little work has been done to predict the performance of SiNW-ISFET sensors. The present study focuses on predicting the performance of the silicon nanowire (SiNW)-based ISFET sensor using four machine learning techniques, namely multilayer perceptron (MLP), nonlinear regression (NLR), support vector regression (SVR) and extra tree regression (ETR). The proposed ML algorithms are trained and validated using experimental measurements of the SiNW-ISFET sensor. The results obtained show a better predictive ability of extra tree regression (ETR) compared to other techniques, with a low RMSE of 1 × 10 mA and an R value of 0.9999725. This prediction study corrects the problems associated with SiNW -ISFET sensors.