In many years, intensive researches have focused on studying the chemical equilibria like complex formation and acid‐base titration in different solvent mixtures, such as methanol‐water. In this respect, it has been revealed that methanol‐water mixture is not a simple homogenous ideal mixture and it contains clusters of pure water (W), pure methanol (M), and associated methanol‐water molecules (MW) with a certain association constant that the solute can distribute among these clusters. To describe solute distribution in this chemical system, an exhausted model has been introduced, which is extended herein to illustrate the distribution of a solute with acid‐base behavior, ie, the neutral red indicator. Since it is imperative to determine the association constant of the solvents and the distribution constants of the solute for calculation of the solute's protonation constant in the mixture, this work employs UV‐vis spectrophotometry as a fast and convenient technique to calculate all these parameters. For this purpose, protonated and deprotonated forms of neutral red are monitored in various water‐methanol compositions. Moreover, the acid‐base equilibrium of neutral red in definite compositions of the solvent mixture is investigated using the data obtained from acid‐base titrations. Finally, the protonation constant of neutral red in MW clusters is determined by analyzing the titration data of three methanol‐water compositions after matrix augmentation and elimination of rank deficiency.