DNA and RNA (or miRNA) are potential biomarkers that could be applied to the diagnosis and treatment of diseases as liquid biopsy toward precision medicine. However, the quantitative detections of the nucleic acid from the liquid sample will be dependent on a well-defined and qualified nucleic acid extraction as sample preparation for the detections/measurements. For nucleic acid extraction, most of the commercial kits rely on silica adsorption as one of the major steps for purification. Unfortunately, the lack of knowledge of the binding mechanism of using silica as an adsorbent for nucleic acids limits the improvements and applications. This study is aiming to explore the adsorption mechanism by adsorption isotherm measurements and thermodynamics information obtained by isothermal titration calorimetry (ITC). This work demonstrates that the mechanistic aspects underlying the adsorption behaviors of DNA with mesoporous silica particles in aqueous solution. We changed the binding parameters, such as pH values, ionic strength, and types of salt and concentrations. We established the adsorption isotherms and measured the binding enthalpy and entropy by ITC at any given binding condition. The elucidated mechanism could provide a better binding condition design for nucleic acid purification and liquid biopsy applications in detection and data transferability.