Three-dimensional (3D) printed splints must be lightweight and adequately ventilated to maximize the patient’s convenience while maintaining requisite strength. The ensuing loss of strength has a substantial impact on the transformation of a solid splint model into a perforated or porous model. Thus, two methods for making perforations—standard approach and topological optimization—are investigated in this study. The objective of this research is to ascertain the impact of different perforation shapes and their distribution as well as topology optimization on the customized splint model. The solid splint models made of various materials have been transformed into porous designs to evaluate their strength by utilizing Finite Element (FE) simulation. This study will have a substantial effect on the designing concept for medical devices as well as other industries such as automobiles and aerospace. The novelty of the research refers to creating the perforations as well as applying topology optimization and 3D printing in practice. According to the comparison of the various materials, PLA had the least amount of deformation and the highest safety factor for all loading directions. Additionally, it was shown that all perforation shapes behave similarly, implying that the perforation shape’s effect is not notably pronounced. However, square perforations seemed to perform the best out of all the perforation shape types. It was also obvious that the topology-optimized hand splint outperformed that with square perforations. The topology-optimized hand splint weighs 26% less than the solid splint, whereas the square-perforated hand splint weighs roughly 12% less. Nevertheless, the user must choose which strategy (standard perforations or topology optimization) to employ based on the available tools and prerequisites.