Aiming at the problem of poor sealing performance in the treatment process of Ordovician aquifer due to improper selection of grouting materials, The differential influence of drilling fluid on the rheological/thixotropic behavior of cement slurry and clay slurry was analyzed from both physical and chemical perspectives through testing methods such as rheology/thixotropy analyzer, particle size distribution analyzer, Zeta potential analyzer, organic carbon adsorption analyzer, and isothermal calorimeter. The sealing effect of drilling fluid on different grouting materials was verified through the application engineering of Mengjin Coal Mine in Xin'an Coalfield. Results show that: (1) Drilling fluid significantly increases the rheological properties (dynamic yield stress, plastic viscosity) and thixotropy of cement slurry and clay slurry, and exhibits a dose-dependent effect. At the same dosage, the rheological parameters of clay slurry are more than 35% higher than those of cement slurry, and the thixotropy is more than 2.5 times higher than that of cement slurry. (2) By analyzing zeta potential and adsorption capacity, cement slurry with positive zeta potential (+1.39 mV) and drilling fluid with negative zeta potential (-35.8 mV) achieved efficient adsorption through electrostatic attraction. The saturated adsorption capacity (330 ppm) and adsorption efficiency (100%) of cement slurry on drilling fluid are 2.4 times and 1.25 times that of clay slurry (-13.4 mV) on drilling fluid, respectively. the decisive role of electrical matching in adsorption behavior was elucidated. (3) Based on electrical matching mechanism, the technology for early adsorption blocking of cement slurry is proposed. The application project in Mengjin coal mine (leakage rate >30 m3/h) of Xin'an coal field shows that the rise rate of hole pressure (0.045 MPa/h) after cement slurry adsorption of drilling fluid is only 5% of that of clay slurry system (0.86 MPa/h), and the plugging response efficiency is improved by 20 times. This study reveals the interaction mechanism between the grouting material and drilling fluid from a multi-scale perspective, and provides a theoretical basis for the design and engineering application of highly efficient plugging materials for the coal mine Ordovician aquifer.