Summary: Systematic enumeration and identification of unique 3D spatial topologies of complex engineering systems (such as automotive cooling systems, electric power trains, satellites, and aero-engines) are essential to navigation of these expansive design spaces with the goal of identifying new spatial configurations that can satisfy challenging system requirements. However, efficient navigation through discrete 3D spatial topology (ST) options is a very challenging problem due to its combinatorial nature and can quickly exceed human cognitive abilities at even moderate complexity levels. This article presents a new, efficient, and scalable design framework that leverages mathematical spatial graph theory to represent, enumerate, and identify distinctive 3D topological classes for a generic 3D engineering system, given its system architecture (SA) – its components and their interconnections. First, spatial graph diagrams (SGDs) are generated for a given SA from zero to a specified maximum number of interconnect crossings. Then, corresponding Yamada polynomials for all the planar SGDs are generated. SGDs are categorized into topological classes, each of which shares a unique Yamada polynomial. Finally, within each topological class, 3D geometric models are generated using the spatial graph diagrams (SGDs) having different numbers of interconnect crossings. Selected case studies are presented to illustrate the different features of our proposed framework, including an industrial engineering design application: ST enumeration of a 3D automotive fuel cell cooling system (AFCS). Design guidelines are also provided for practicing engineers to aid the application of this framework to different types of real-world problems such as configuration design and spatial packaging optimization.