Sequential aligners (SAs) introduced about a decade ago, changed the practice of orthodontics as we knew it but the adverse events and reactions (AER) associated with SA is not known. The Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database is a reliable database that has AERs reported. The manuscript attempts to review the AER associated with SA using the MAUDE database. The authors downloaded and reviewed the SA-related AER from MAUDE for a period of 5 years. In-depth analysis of the site and nature of intraoral and extraoral AERs were performed. We attempted to calculate the probability of pathologies being directly related to SA use, using Bayes' theorem. In the study period of 5 years, 175 cases of AER registered with MAUDE database owing to use of SA. Of the 175 cases, 129 (73.71%) instances were mandatory reports filed by the manufacturer. Of all AERs, 32 (18.29%) cases had been diagnosed/suspected to have an allergic reaction, 20 (11.43%) of them with anaphylactic reaction and 4 (2.29%) of them with angioedema. Lesions involving tongue, throat, and lip such as soreness, inflammation, and hives were more commonly reported. In addition, 12 cases (6.86%) reported of nausea, 11 (6.29%) of gastrointestinal issues (stomach upset, diarrhea, and vomiting), 13 (7.43%) of neuromuscular issues (muscle cramps, spasm, and pain), 13 (7.43%) of cough, 10 (5.71%) of persistent headache, 3 (1.71%) of fever, and 12 (6.86%) of cardiac-related issues were identified. The AERs associated with SA has been described. Though the MAUDE database is not an exact, wholesome and reliable source to identify the potential AER, currently, it is the only available source of AERs associated with SA use. The nature of AERs with the use of SA and its potential pathogenesis and implications has been discussed.