In recent years, various studies have been conducted to investigate the relationship between erythropoiesis-stimulating agents (ESAs) and mortality in hemodialysis patients, who showed contradictory results. Therefore, this study aimed to investigate the relationship between ESAs and mortality in hemodialysis patients. The current study is a systematic review and meta-analysis based on observational and interventional studies published in the Web of Science, Cochrane Library, Science Direct, PubMed, Scopus, and Google Scholar databases between 1980 and the end of 2022. Jadad scale checklist and Newcastle Ottawa scale were used to evaluate the quality of articles. The study data were analyzed using Stata 15 software. In the initial search, 3933 articles were extracted, and by screening and considering the research criteria, 68 studies were finally included in the meta-analysis. According to the meta-analysis results, the risk ratio (RR) of overall mortality in hemodialysis patients receiving ESAs was equal to 1.19 (95% CI: 1.16-1.23, P ≤ 0.001). The RR of mortality in patients aged 60 years and under was equal to 1.33 (1.15-1.55, P ≤ 0.001), in the age group over 60 years was equal to 1.13 (1.10-1.16, P ≤ 0.001), in randomized clinical trial studies was equal to 1.06 (0.80-1.40, P = 0.701), in cohort studies was equal to 1.20 (1.16-1.25, P ≤ 0.001), in American countries was equal to 1.19 (1.10-1.29, P ≤ 0.001), in Asian countries was equal to 1.15 (1.10-1.19, P ≤ 0.001), and in European countries was equal to 1.18 (1.05-1.34, P = 0.007). The results of the study show that receiving ESAs is associated with a 19% increase in the risk of overall mortality in hemodialysis patients.