<p>In this study, quaternary ammonium salts-based deep eutectic solvent (DESs) were used as the research object. The thermodynamic properties of the binary mixture formed by DESs and acetonitrile (ACN) were systematically studied. By characterizing fundamental physicochemical properties, this work establishes a foundational theoretical basis for the practical application of such DESs. In this work, the density, surface tension, and electrical conductivity of binary mixtures of tetramethylammonium chloride:formic acid ([TC:FA]+ACN), tetramethylammonium chloride:1,2-propanediol ([TC:PP]+ACN), and tetramethylammonium chloride:triethanolamine ([TC:TA]+ACN) were measured. The excess molar volume (<i>V</i>^E), molar surface Gibbs energy (<i>g</i>_s), and molar electrical conductivity (<i>Λ</i>_m) of all mixed systems were obtained using the measured experimental data. Through the quantitative analysis of derivative parameters such as excess molar volume, the interaction mechanism between DESs and ACN was clarified. According to the theoretical model of surface tension prediction, the correlation between the predicted value of the surface tension and the experimental value was verified. The conductor-like screening model for real solvents (COSMO-RS) was used to explore the specific interaction between all DESs and organic solvents. This basic research not only provides key basic physical data for the industrial application of DESs, but also provides an important theoretical basis for system design and process optimization in the fields of extraction separation and electrochemistry.</p>