The objective of this paper is to present a new process synthesis tool to systematically synthesize, design, and evaluate plant layouts for early-stage design/retrofit of wastewater treatment plants. The tool relies upon an integrated methodology with the following key features: (1) first-principles mechanistic models used to simulate existing and emerging technologies. This key innovation ensures predictive capability, (2) Monte Carlo technique and simulation-based optimization techniques for handling the resulting computational complexity effectively, (3) a systematic initialization algorithm developed for plant-wide simulation, (4) optimizing design parameters, operational conditions, and plant layout simultaneously. Moreover, stochastic analysis is performed to verify the robustness of plant configuration and design proposed by the tool. Finally, using the tool, three real case studies are analyzed to demonstrate the design retrofit of WWTP to the energy recovery plant. (C) 2020 Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.