Introduction: Healthy individuals' short-term wear of mandibular advancement appliance (MAD) induces neuroplastic changes in the corticomotor pathway. MAD is recommended to manage patients with obstructive sleep apnea (OSA) and might be associated with central motor changes. Aim: Assess the corticomotor plasticity of the masseter and tongue pathway due to short-term use of MAD in OSA patients. Materials and Methods: Twenty-eight mild or moderate OSA adult patients without the presence of chronic orofacial pain or headache or uncontrolled systemic conditions participated in this randomized placebo-controlled crossover study. The participants used a MAD at 40% of a maximal protrusion (MAD active) followed by two weeks of a MAD without any jaw protrusion (MAD placebo) or vice-versa during sleep. There was a wash-out period of two weeks between the two positions. Assessments were made at baseline, after MAD active, and after MAD placebo. Transcranial magnetic stimulation (TMS) assessed the amplitude of motor evoked potential (MEP) on the right masseter, tongue, and first dorsal interosseous (FDI). Repeated-measures ANOVA assessed differences in MEPs for each site. Moreover, differences in the map MEP volume were evaluated. Multiple comparison analyses were performed using Tukey's Honestly Statistical Difference. Results: There were no significant MEP amplitude changes for the hand (p = 0.129). However, the MAD position was significantly affected for both masseter and tongue (p < 0.001) corticomotor excitability. There was an increase in the MEP amplitude following the MAD active when compared to baseline and MAD placebo position (p < 0.001). In contrast, there were no differences between baseline and placebo positions (p > 0.050). Finally, the MAD position (p < 0.001) had a significant main effect on the map volume. There was an increase in the MEP amplitude following the MAD active position compared to the baseline and MAD placebo position. The FDI presented the biggest map volume (p < 0.003). Conclusion: MAD can induce neuroplastic changes in the corticomotor pathways in mild to moderate OSA patients, indicating potential central mechanisms. These findings can contribute to further understanding of the mechanisms of action of oral appliances to treat OSA.