Membrane proteins (MPs) are involved in many essential biomolecule mechanisms as a pivotal factor in enabling the small molecule and signal transport between the two sides of the biological membrane; this is the reason that a large portion of modern medicinal drugs target MPs. Therefore, accurately identifying the membrane protein-ligand binding sites (MPLs) will significantly improve drug discovery. In this paper, we propose a sequence-based MPLs predictor called MPLs-Pred, where evolutionary profiles, topology structure, physicochemical properties, and primary sequence segment descriptors are combined as features applied to a random forest classifier, and an under-sampling scheme is used to enhance the classification capability with imbalanced samples. Additional ligand-specific models were taken into consideration in refining the prediction. The corresponding experimental results based on our method achieved an appreciable performance, with 0.63 MCC (Matthews correlation coefficient) as the overall prediction precision, and those values were 0.604, 0.7, and 0.692, respectively, for the three main types of ligands: drugs, metal ions, and biomacromolecules. MPLs-Pred is freely accessible at http://icdtools.nenu.edu.cn/.