A systematic holistic mathematical programming (HMP) is proposed to formulate a mixed integer nonlinear programming (MINLP) model for one-step optimization of water-allocation and heat exchange network (WAHEN) designs with single- or multi-contaminant water streams. The proposed model formulation and solution strategy are believed to be superior to the available ones in the following aspects. First, a comprehensive representation combining two separate superstructures is adopted to capture the structural characteristics of the integrated WAHEN. Then, a hybrid optimization strategy integrating stochastic and deterministic components is developed for the resulting MINLP model and, also, an interactive iteration method is adopted based on sensitivity analysis to guide the search toward a potential global optimum. Finally, evolutionary strategies and manipulations are executed to enhance WAHEN configurations. Two illustrative examples are presented to demonstrate the validity and advantages of the proposed approach.