Among treatments in the literature for myofascial pain syndrome (MPS), the most reliable therapies in dentistry are spray and stretch, and, although less frequently used, anesthetic injection. Adult MPS subjects are often treated using fixed orthodontic therapy for resolution of malocclusion. There is no clarity in the literature on the prognosis of MPS during orthodontic therapy. The purpose of this study was to analyze the prognosis of MPS during orthodontic treatment of subjects with malocclusion, initially diagnosed as having MPS. The analysis covered the medical records of 91 young adult Caucasians scheduled for orthodontic treatment for various malocclusions. Thirty-seven of the patients were initially diagnosed as also having MPS (T0). Thirty patients began the orthodontic treatment and were recalled for a re-evaluation of MPS after dental alignment and dental class correction was achieved (T1). A wait-and-see strategy was applied in seven subjects who were included as the control subjects. They received no treatment for MPS. At T1, a statistically significant decrease was observed in the study group in the presence of any clicking or creaking noises from the jaw joint, a significant jaw joint and jaw muscle pain reduction, and a quality of life improvement. Among patients who were depressed at the beginning of treatment, the majority felt better at the follow-up evaluation. On muscular palpation, a statistically significant decrease was found on the visual analogic scale value of the middle fibers of the temporalis muscle, temporalis tendon, clavicular and sternal division of the sternocleidomastoid muscle, masseter muscles, and posterior cervical muscles. The temporalis and the masseter muscles showed a significant decrease in the number of subjects with trigger points (TrPs) in all areas in the study group, after treatment. The digastric and sternocleidomastoid muscles also showed a significant reduction in the number of subjects with TrPs. Subjects with MPS and malocclusion were treated using a fixed orthodontic treatment. They showed improvement, although no resolution, in the signs and symptoms of MPS, compared with the untreated control group.