This study aimed to investigate the changes of serum interleukin-21 (IL-21) levels in patients with chronic hepatitis B (CHB) under the conditions of virological response, hepatitis B E antigen (HBeAg) seroconversion and viral relapse after treatment with nucleoside (acid) analogues (NAs). It searched PubMed, Cochrane Library, Embase, Web of Science, Springer Link, CNKI, CBM, Wanfang, WIP, Duxiu, and other databases from January 2010 to October 2024. Literature screening, data extraction and quality evaluation were carried out according to the inclusion criteria, and Meta-analysis was conducted by Review Manager 5.4 software. The level of IL-21 in HBV DNA complete response group was significantly higher than that in HBV DNA incomplete response group (RR ＝ 24.94, 95% CI [20.09, 29.80 ], Z ＝ 10.07, P<0.01), and the level of IL-21 in HBeAg negative group was significantly higher than that in HBeAg positive group (RR ＝ 34.22, 95% CI [29.01, 39.44]，Z＝12.86，P＜0.01), IL-21 was significantly higher in the virological sustained response group than in the virological relapse group (RR ＝－13.07, 95% CI [－15.51, －10.62], Z＝10.47, P<0.01). Serum IL-21 can be used as an effective biomarker to evaluate the therapeutic effect of patients, to assist in the adjustment of antiviral therapy and to evaluate the prognosis of patients.