The human (h)SMC5/6 complex is one of the most enigmatic members of the SMC family of chromosome organizing complexes. It performs essential functions in the maintenance of genome stability and higher-order chromatin organization. Despite its functional significance, challenges in recombinant expression and purification of biologically active complex have limited structural and functional analysis of the human enzyme. Here, we present a robust yeast-based expression approach for high-level production and purification of recombinant hSMC5/6 core complex. We employed a subunit fusion approach coupled with affinity tag/linker removal steps to successfully express and purify near native hSMC5/6 complex from Saccharomyces cerevisiae. This bespoke purification approach takes advantage of triple-affinity tag purification steps and size exclusion chromatography to yield >95% pure protein with stoichiometric homogeneity. The workflow is scalable and enables efficient production of a functionally active recombinant enzyme, facilitating downstream structural and functional studies. The strategy developed to purify the hSMC5/6 core complex is broadly applicable to other difficult-to-express multi-subunit enzymes of similar size and complexity, demonstrating the utility of yeast-based microbial cell factories for the expression of human protein complexes.