Objective To mine the adverse drug event (ADE) signals of commonly used 5-hydroxytryptamine 3 receptor antagonists (5-HT3RA), including ondansetron, granisetron, palonosetron and dolasetron, and to explore the relationship between adverse events and drugs to provide references for clinical medication decisions.Methods The data of ADE reported in the Adverse Event Reporting System (FAERS) were extracted from the first quarter of 2016 to the last quarter of 2020, 20 quarters in total. The reported odds ratio (ROR) and medicines and healthcare products regulatory agency method (MHRA) were used to mine the adverse drug event signals of the above mentioned four 5-HT3RAs. The Medical Dictionary for Regulatory Activities (MedDRA) was used to standardize and unify the terms of ADE. Analyze and compare the adverse reaction signals obtained from the screening.Results Totally 991 ADE signals of ondansetron were obtained, involving 25 system organ classes (SOCs). The signals that should be paid close attention to in clinic included congenital, familial and genetic disorders and fetal exposure during pregnancy. Totally 54 ADE signals of granisetron were obtained, involving 10 SOCs. The signals that should be paid close attention to in clinic included the way of drug use, various reactions of topical drug site and gastrointestinal reactions. Just one ADE signal which belonged to the blood and lymphatic system disorders of palonosetron were obtained, with 5 cases reported.Conclusion The main systems and organs involved in ADE signals of the three drugs were significantly different. Ondansetron involved more SOCs than granisetron and palonosetron. It should be noted that the use of ondansetron during pregnancy may be teratogenic. When using this type of drugs as antiemetics, it is recommended to conduct a pre-medication evaluation of the patients, including the underlying disease in the assessment, and pay close attention to the patient's vital indicators during the medication process. Ondansetron should be avoided during pregnancy.