Water activity in aqueous solutions containing diphenhydraminehydrochloride, DPH-HCl, (D+)-galactose, (D−)-fructose, (D+)-lactose, and sucrose was measured using an improved isopiestic method at T = 298.15 K. Vapor pressure values were calculated from the measured water activity data. Nonrandom two-liquid (NRTL), NRF-NRTL, mNRTL, Wilson, TNRF-mNRTL and modified NRTL proposed by Xu local composition-based models were applied for correlating the water activity data for binary and ternary aqueous solutions containing the DPH-HCl drug and saccharides considered in this work. All of these models satisfactorily predicted the water activity data for the systems investigated. Water activity data and decreasing vapor pressure were utilized to highlight the solute−solvent interactions.