Proton transfer free energies and proton transfer enthalpies at the interface of different solvents are very important in chemistry and biology. In the present work, we present a general model to describe theoretically the proton transfer at the interface of two given solvents. The model is simple to apply, affordable and stable. It is based on first principles calculations of neutral and protonated clusters of the solvent molecules. The model is described and applied to the calculation of the water-methanol proton transfer free energy and enthalpy at standard conditions. We have thoroughly explored the potential energy surfaces (PESs) of neutral and protonated water clusters as well as neutral and protonated methanol clusters in the solvent phase. The located structures have been optimized at the MN15/6-31++G(d,p) level of theory. Using the favourable structures and the proposed model, the water-methanol proton transfer free energy and enthalpy are evaluated to be −6.1 kJ mol−1 and −13.3 kJ mol−1, respectively. The calculated water-methanol proton transfer enthalpy is found to be in excellent agreement with the experimental estimate of −15.9 kJ mol−1, based on the tetraphenylarsonium-tetraphenylborate (TATB) approach.