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Background drug overdose is a common type of medication error, which caused significant patient injuries and economic losses. To determine which drugs are reported most frequently in association with drug overdose, a comprehensive search was conducted in the FDA Adverse Event Reporting System (FAERS) database. The study also sought to determine the top 10 drugs reported with drug overdose. Methods FAERS database was searched for drug overdose records submitted from the first quarter of 2017 to the fourth quarter of 2021. Descriptive analyses were conducted based on the total counts and percentages of reports associated with the drug. Subgroup analyses were performed on drugs of different pharmacological classifications. Results A total of 170,424 drug overdose reports were retrieved. The results revealed that antipyretics and analgesics took the highest risk for overdose, with 63,143 (37.05%) cases reported. Among them, opioids were associated with the most drug overdose events. The top 10 drug classes relating to drug overdose in FAERS were opioid analgesic, anilide antipyretic analgesic, 5-HT reuptake inhibitors, bronchodilators, monoclonal antibodies and antibody-drug conjugates, benzodiazepines, antipsychotics, GABA derivatives, antimanic agents, and propionic acid derivatives. Conclusion to reduce the occurrence of drug overdose events, some methods could be considered including applying a pre-prescription review system, drug safety education, developing warning lists, etc.