Systematic enumeration and identification of unique 3D spatial topologies of complex engineering systems such as automotive cooling layouts, hybrid-electric power trains, and aero-engines are essential to search their exhaustive design spaces to identify spatial topologies that can satisfy challenging system requirements. However, efficient navigation through discrete 3D spatial topology options is a very challenging problem due to its combinatorial nature and can quickly exceed human cognitive abilities at even moderate complexity levels. Here we present a new, efficient, and generic design framework that utilizes mathematical spatial graph theory to represent, enumerate, and identify distinctive 3D topological classes for an abstract engineering system, given its system architecture (SA) – its components and interconnections. Spatial graph diagrams (SGDs) are generated for a given SA from zero to a specified maximum crossing number. Corresponding Yamada polynomials for all the planar SGDs are then generated. SGDs are categorized into topological classes, each of which shares a unique Yamada polynomial. Finally, for each topological class, one 3D geometric model is generated for an SGD with the fewest interconnect crossings. Several case studies are shown to illustrate the different features of our proposed framework. Design guidelines are also provided for practicing engineers to aid the utilization of this framework for application to different types of real-world problems.