Objective To explore and compare the post-marketing adverse event (AE) signals of four mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors (binimetinib, cobimetinib, trametinib, and selumetinib) based on the FDA Adverse Event Reporting System (FAERS) database, so as to provide a reference for clinical medication safety.Methods The AE reports from the first quarter of 2004 to the first quarter of 2023 with the above mentioned MEK inhibitors as the primary suspected drugs were extracted from the FAERS database, and the suspicious risk signals were mined by the OpenVigil 2.1 online tool through the reporting odds ratio (ROR) method and proportional reporting ratio (PRR) method. A comparative analysis of AE risk signals among the four MEK inhibitors was conducted.Results As of the first quarter of 2023, the FAERS recorded 2 409, 2 091, 940, and 406 AE reports with trametinib, binimetinib, cobimetinib, and selumetinib as the primary suspected drugs, respectively. A total of 386 statistically significant AE signals (trametinib: 184, binimetinib: 85, cobimetinib: 80, selumetinib: 37) were identified by ROR and PRR methods. The most frequently affected system organ classes (SOC) included skin and subcutaneous tissue diseases, eye organ diseases, various examinations, systemic diseases and various reactions at the administration site, gastrointestinal diseases. The majority of frequently reported AEs for the four MEK inhibitors were consistent with those described in the drug labels. Newly identified AE signals included infections, peripheral neuropathy, acute kidney injury, and menstrual irregularities. While the four MEK inhibitors exhibited similar SOC profiles, differences were observed in reporting frequencies. Trametinib demonstrated unique psychiatric and endocrine system AE signals, whereas selumetinib showed distinct reproductive system and breast disorder AE signals.Conclusion This study systematically analyzed and compared the AE signal profiles of four MEK inhibitors based on the FAERS database, revealing both shared and drug-specific safety characteristics. These findings highlight the need for clinicians to be alert to the risk of adverse drug events during clinical use, and to implement individualized treatment strategies based on patient-specific factors.