The development of digital technologies has allowed for the fabrication of new materials; however, it makes it difficult to choose the best methods to obtain occlusal splints with optimal properties, so it is essential to evaluate the effectiveness of these materials. The aim of the study is to compare the fracture resistance of occlusal splints made of different materials after thermo-mechanical aging. Methods: A total of 32 samples were made from 4 materials (two 3D printed polymeric materials, a PMMA disc for CAD/CAM, and a conventional heat-cured acrylic resin); subsequently, the fracture test was performed using the load compression mode applied occlusally on the splint surface. Statistical analysis: Four statistical tests were used (Shapiro-Wilk, Levene’s test, ANOVA, and Tukey’s HSD test). Results: The following study showed that there are differences in fracture strength among the four materials investigated, where the highest strength was observed in the milled splint, with a mean of 3051.2 N (newton) compared to the strength of the flexible splint with 1943.4 N, the printed splint with 1489.9 N, and the conventional acrylic splint with 1303.9 N. Conclusions: The milled splints were the most resistant to fracture. Of the printed splints, the splint made with flexural rigid resin withstood the applied forces in acceptable ranges, so its clinical indication may be viable. Although the results of this research indicated differences in the mechanical properties between the CAD/CAM and conventional fabrication methods, the selection may also be influenced by processing time and cost, since with a CAD/CAM system there is a significant reduction in the production time of the splint material.