Background/Objectives: The relation between the orthopedic temporomandibular joint (TMJ) instability and temporomandibular disorder (TMD) most commonly remain unrecognized by orthodontists. In this study we aimed to evaluate the dentofacial characteristics and temporomandibular disorder symptomatology of patients with orthopedic instability before and after deprogramming with a stabilization splint. Methods: Sixty patients with the signs and symptoms of TMD were assessed using the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and underwent stabilization splint therapy to place the condyles in a more stable musculoskeletal position. The extent of condylar displacement was evaluated using the condylar position indicator (CPI). Sixteen angular and linear hard tissue landmarks were traced and compared from lateral cephalograms taken in the maximum intercuspation (MI) position before, and in the centric relation (CR) position after, the splint therapy. Results: Following the splint therapy, the signs and symptoms of TMD were significantly reduced or completely eliminated in more than 90% of patients. Compared with the values registered before the splint therapy, a significant reduction in the mean values of condylar displacement was observed on both sides of the vertical (p < 0.001), horizontal (p < 0.05), and transverse (p < 0.001) planes of space after the splint therapy. A comparison of pre- and post-splint lateral cephalograms revealed that, following the splint therapy, the mandible moved more posteriorly and rotated in a more clockwise direction. Conclusion: In patients with orthopedic instability and the signs and symptoms of TMD, muscle deprogramming with a stabilization splint therapy is highly recommended to improve the health of the temporomandibular joint and masticatory structures and contribute to a more correct orthodontic diagnosis.