Ketoconazole (KNZ) and miconazole (MNZ) are two of the most common topical and vaginal antifungal drugs in clinical use. Although they are imidazoles of extremely low aqueous solubility, they are presented in various pharmaceutical formulations. The purpose of this work is to analyze the solute-solvent interactions in pure solvents and the effect of temperature on KNZ and MNZ in buffer solutions at physiological pH. The study was carried out using solvatochromic and thermochromic techniques, and the multiparametric statistical analysis was performed with the method of linear solvation energy relationship of Kamlet and Taft and the Catalan method. The results showed a hypsochromic shift as the polarity of the solvents decreases. The highest relative contribution in KNZ by means of the Kamlet and Taft equation was due to the π parameter, while in MNZ it was the SP parameter by means of the Catalan equation. The thermochromic study of KNZ at physiological pH 5.00 and 7.40 allowed us to visualize a considerable increase in absorbance as temperature rises, without isosbestic points or crossovers. KNZ polarity/polarizability and MNZ polarizability are highlighted as the main non-specific interactions in solution. The hypsochromic shift observed shows that the excited state in solution is of lower polarity and higher energy than the basal state. The absorbance of KNZ observed at pH 5.00 corresponds to the highest concentration of the BH⁺ species, while at pH 7.40 it is due to the predominance of the B molecular species.