Mud cake is formed by the accumulation of particles on the surface and inside of the well wall during the filtration of drilling fluids, which is multiply affected by reservoir types, composition of drilling fluids, and wellbore conditions. Numerical simulation can provide a more comprehensive study than experiments, but the usual single-phase models of drilling fluid is difficult to simulate the non-homogeneous characteristics of mud cake. In this paper, the calculation method of interactions between particles and the drag force on particles with different sphericity in non-Newtonian fluid are derived. Therefore, a solid-liquid two-phase flow model of drilling fluid that describes the motion of solid and liquid phases, respectively, is constructed to investigate the influences of their properties on the dynamic non-homogeneous formation of mud cake in the real pore space of cores. The results show that the flow volume and velocity of the liquid phase are affected by the tortuosity of the pore channel, which in turn affects the entering number of particles. The influences of particle parameters on the entering number are radius > morphology > release velocity > free energy of the surface > density > release concentration. The solid-liquid two-phase flow model can refine the analysis to formulate the most applicable drilling fluids, which will significantly reduce the exploration and validation work of plugging experiments.