Introduction: Eplerenone is approved for the treatment of hypertension as well as symptomatic heart failure with reduced ejection fraction (HFrEF) following an acute myocardial infarction. However, the adverse events (AEs) have not been systematically analyzed. The aim of this study was to identify adverse drug reactions (ADRs) related to eplerenone using the FDA Adverse Event Reporting System (FAERS) database. By identifying previously unreported AEs, the study could potentially contribute to updating the drug's label. Methods: In order to find significant AEs, four algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN) and Empirical Bayesian Geometric Mean (EBGM), were used to analyze the signal strength of the ADRs connected to eplerenone that were gathered from the FAERS database over the previous 20years. Results: From 2004Q1 to 2023Q4, a total of 20, 629, 811 reported cases were gathered from the FAERS database for this study. After processing the data and filtering, 1,874 case reports were analyzed. Of these cases, 1,070 AEs were identified, 128 of which were eplerenone-related ADRs. We investigated the occurrence of ADRs induced by eplerenone in 27 organ systems. Our study showed that the AEs listed in the medication's package insert correspond with those listed in the literature, including hyperkalemia and increased creatinine. Additionally, the prescription label for eplerenone does not include all system organ class (SOC) terms, like Vascular disorders, hepatobiliary Disorders, etc. Discussion: The study used multiple algorithms to quantify the signal strength and then identified any previously unrecognized ADRs, further studies are needed to confirm the association of ADRs with eplerenone. The findings of this study may provide important insights into the safety profile of eplerenone, ensure that healthcare providers have up-to-date information about their potential risks and help guide them in the correct use of the drug.