Addressing the long-standing ambiguity in the design of plugging agent dosage for high-water-cut reservoirs—constrained by factors such as insufficient understanding of channeling pathways—this study leverages seepage mechanics theory and well test interpretation data. By investigating the synergistic mechanism between reservoir heterogeneity and plugging agent dosage, we clarified the synergistic control mechanism of the “dual resistance zones” between injection and production wells, and proposed a synergistic target framework: “reservoir heterogeneity—pressure and pressure gradient distribution—profile control to reconstruct the displacement system—dosage of particle and gel plugging agents.” On this basis, the determination criterion for the reasonable profile control radius was provided by systematically analyzing the relationship between the reasonable profile control radius and the development radius of advantage channel. We established dosage calculation models for plugging agents: the equivalent volume method (for particles) and the modified volume method (for gels), and developed a matching relationship between particle size (for particle plugging agents) and fracture aperture. Ultimately, a multi-dimensional synergistic design method for reasonable plugging agent dosage was proposed. Field application and subsequent follow-up evaluation studies have demonstrated that the plugging agent dosage designed by this method for target wells is 0.21~3.53 t/well for particles and 93.51~2399 m³/well for gels. After the implementation of profile control and water plugging measures, the pressure rise was reasonable, and the injection proceeded smoothly. The consistency between well test interpretation results and construction performance reached over 90%, achieving remarkable water control and oil stabilization effects. The research results provide technical support for water control and oil stabilization in high-water-cut reservoirs, and can improve the feasibility of profile control and water plugging design schemes for similar reservoirs by more than 30%.