This study develops a generalized superstructure and a compact mixed-integer nonlinear programming (MINLP) model for achieving efficient energy and water utilization in designing integrated process water systems with large sizes. Utilizing non-isothermal mixing reduces the need for many heat exchangers for indirect heat recovery. Hence, an exchanger-centric modeling strategy for heat integration is embraced over a hot–cold streams matching-based approach. A novel two-step approach is proposed to address the nonconvex and nonlinear challenges and ensure the efficiency of getting high-quality solutions. Initially, a targeting model incorporating linear heat integration is adopted to reduce the superstructure and partially initialize the design model. Subsequently, in the synthesizing stage, a two-level global search procedure is devised, integrating adaptive exchanger adjustment with multi-start local optimization. The robustness and efficiency of the proposed approach are confirmed through the resolution of four large-scale problems within one hour, yielding improved results compared to the best-known existing solutions.