Water plugging was an important but difficult process close to high-water-cut production wells. The injected water-plugging materials were usually liquid and typically had been evaluated by conventional water-flooding experiments. In this study, silicon dioxide (SiO2)/polystyrene hydrophobic insoluble microsphere particles were introduced as a selective water shutoff agent, and the water-saturated core was flooded with a high-water-cut oil–water mixture. Indexes such as modified oil-coning time, water-cut fluctuation, and cumulative water cut were proposed to evaluate water-plugging capability. A parametric study was conducted to evaluate the influence of particle composition (A, SiO2/polystyrene particle; B, complete polystyrene particle), water cut of the injected oil–water mixture, and preheating temperature of the insoluble particles on water-plugging performance. The results from the index analysis and relative permeability curve showed that the proposed indexes could be used to compare water-plugging performance during oil–water mixture drive; both particles had better water-plugging performance when the injected mixture was not an ultrahigh water cut (fw < 90%). Particle B had larger lipophilicity and stronger capacity for decreasing the water cut (about 0.55–1.28%) at a conventional temperature when the oil–water mixture of the injected fluid had a water cut of 90%. Particle A had lower capacity to decrease the water cut (by about −0.94–0.26%), but it was resistant to reservoir temperature because of its dense structure and the addition of SiO2. These results provided suggestions for the application of hydrophobic insoluble microsphere particles in water plugging in production wells.