The present study aims at developing a quantitative structure–activity relationship (QSAR) model for the determination of gut permeability of 228 pharmacological drugs at different pH conditions (3, 5, 7.4, 9, intrinsic). As a consequence, five different datasets (according to the diverse permeability shown by the compounds at the different pH values) were handled, with the aim of discriminating compounds as low-permeable or high-permeable. In order to achieve this goal, molecular descriptors for all the investigated compounds were computed and then classification models calculated by means of partial least squares discriminant analysis (PLS-DA). A high predictive capability was achieved for all models, providing correct classification rates in external validation between 80% and 96%. In order to test whether a reduction in the molecular descriptors would improve predictions and provide information about the most relevant variables, a feature selection approach, covariance selection, was used to select the most relevant subsets of predictors. This led to a slight improvement in the predictive accuracies, and it has indicated that the most relevant descriptors for the discrimination of the investigated compounds into low- and high-permeable were associated with the 2D and 3D structures.