Origami has unfolded engineering applications in various fields, such as electrical, civil, aerospace, biomedical, and materials engineering. Those applications take advantage of the origami shape change capabilities to create tunable, deployable, and multifunctional systems. Although origami has catalyzed innovative solutions for such systems, its feasibility is challenged by pervasive pragmatic aspects. Thus, this thesis focuses on practical aspects that must be addressed for multifunctional origami applications, such as geometric imperfections, manufacturing, multiphysics considerations, and actuation strategies across scales. Specifically, it provides an in-depth study of geometric imperfections that may occur during the fabrication or service of origami systems and investigates how such inevitable imperfections impact both geometric and mechanical properties of origami patterns. Regarding manufacturing, we bring origami to the micro-scale and create architected metamaterials with remarkable mechanical properties, e.g., stiffness and Poisson’s ratio tunable anisotropy, a significant degree of shape recoverability, and reversible auxeticity. On the multiphysics front, we examine the coupling of mechanical and electromagnetic fields by using origami to fabricate spatial filters – frequency selective surfaces with dipole resonant elements placed across the pattern fold lines. The electrical length of the dipole elements changes as the pattern changes folding states, facilitating tunable frequency responses. Finally, we propose an untethered actuation solution with direct applications to origami robotics. Our solution couples geometric bi-stability and magnetic-responsive materials, allowing for instantaneous shape locking and local/distributed actuation with controllable speed, which can be as fast as a tenth of a second. The proposed actuation leads to direct application to robots capable of shape-changing, computing, and sensing.