In this study, the chromatographic retention behavior and dissociation constants (pKa) of H2 receptor antagonists ranitidine and famotidine were determined by the green reverse phase liquid chromatography (RPLC) and hybrid micellar chromatography methods, which are widely used today. Replicate analyses were performed on a Gemini NX C18 (250 × 3.0 mm ID, 5 μm) column at constant temperature (37 °C) and flow rate (1 mL/min). The obtained data analyses were evaluated with the linear solvation energy relationship (LSER) approach and the consistency of the data was assessed by calculating the theoretical retention time values. The (Formula presented.) and (Formula presented.) values obtained in ethanol–water binary mixtures containing 11%, 13%, 15%, and 20% (v/v) ethanol were also calculated with this approach. The pKa values of these compounds in water and pure micellar environment were calculated with (Formula presented.) values and solvent. It was observed that the (Formula presented.) data obtained by three different methods were compatible. Accordingly, with the hybrid micelles method, (Formula presented.) and (Formula presented.) values for famotidine were calculated as 7.305 and 9.869, respectively, and (Formula presented.) and (Formula presented.) values for ranitidine were calculated as 2.952 and 8.589. The environmental impacts of the methods applied in the study were evaluated using green metric tools.