The need to optimize the geometry and topology of construction components and assemblies can often be framed as combinatorial optimization problems (COPs). Such COPs occur throughout construction and are particularly relevant in architectural panel systems, given the complexity of panel topology, large component quantity in most projects, and the need to reduce waste produced during fabrication. The contribution of this paper is the development of novel combinatorial optimization algorithms for unfolding and nesting panels: a process that is central to realizing a fully automated and optimized file-to-factory system. The first algorithm for panel unfolding explores both enumerative and metaheuristic optimization to determine circumstances and applications where each are favorable. Then, a modified two-dimensional (2D) cutting stock algorithm using metaheuristics is developed for deriving optimal nest …