While computational fluid dynamics (CFD)‐based compartment models have gained popularity as a cost‐effective alternative to full CFD modeling of complex mixing systems, model development involves significant trial‐and‐error efforts. This work presents a generalized zoning framework for the streamlined development of CFD‐based compartment models with detailed characterization of the reduced‐order representation of the flow physics. With a stirred tank as an illustrative case, reduced‐order model for species transport and heat transfer with turbulent flow is derived, followed by introducing the generalized zoning framework to demonstrate how a reduced‐order compartment model can be constructed based on a simplified CFD simulation. A test case of mixing two miscible thermal fluids is used to evaluate the CFD‐based compartment model. The results demonstrate that the proposed zoning framework exhibits an accurate representation of the CFD simulation of hydrodynamics and demonstrates capabilities of capturing species and heat transfer in turbulent flow systems with complex geometric configurations.