Background. In recent years, a large amount of clinical evidence and animal experiments have demonstrated the unique advantages of mineralocorticoid receptor antagonists (MRA) for treating chronic kidney disease (CKD). Aims. Accordingly, the present study aimed to systematically assess the second-generation selective MRAs eplerenone’s safety and effectiveness for treating CKD. Methods. Four databases (PubMed, The Cochrane Library, Embase, and Web of Science) were searched for randomized controlled trials (RCT) correlated with eplerenone for treating CKD up to September 21, 2022. By complying with the inclusion and exclusion criteria, literature screening, and data extraction were conducted. Results. A total of 19 randomized controlled articles involving 4501 cases were covered. As suggested from the meta-analysis, significant differences were reported with the 24-h urine protein (MD = −42.23, 95% confidence interval [CI] = -76.72 to −7.73, P = 0.02), urinary albumin-creatinine ratio (UACR) (MD = −23.57, 95% CI = −29.28 to −17.86, P