Introduction: Depression can impact prolactin (PRL) levels by activating the body's stress response and releasing stress hormones like cortisol, which disrupt normal PRL regulation. PRL plays a role in various physiological systems, including reproduction, metabolism, immune regulation, and neurogenesis. Previous studies on PRL levels in depressive patients have yielded contradictory results. This meta-analysis aims to evaluate PRL concentrations in depressive patients versus healthy controls. Methods: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was conducted across multiple databases, including PubMed, Scopus, Web of Science, Embase, PsycINFO, CINAHL, ProQuest, Science Direct, and Google Scholar, up to 2024. Review Manager 5.3, Jamovi, and Open Meta Analyst software were utilized to calculate the standard mean difference (SMD) and assess heterogeneity, publication bias (via funnel plots and Egger's test), subgroup analysis, sensitivity analysis, and meta-regression. Results: Sixteen studies with a combined population (n) of 1492 (776 depressive disorder patients and 716 controls) met the inclusion criteria for serum or plasma PRL. This meta-analysis indicates a statistically significant SMD in serum or plasma PRL between depressed patients and controls, with a pooled SMD of 0.44 (95 % CI:- 0.20 to 0.68, p = 0.0003). Conclusions: This meta-analysis found a statistically significant difference in serum or plasma PRL levels between individuals with depressive disorders. Further research is warranted to explore the potential of PRL as a biomarker for depression diagnosis or severity, as well as its therapeutic implications. Additionally, investigating the underlying mechanisms of PRL dysregulation in depression may lead to the development of novel treatment strategies.