Background <p>Lowering bodily iron stores through phlebotomy is a nursing-led procedure widely used to treat and manage hemochromatosis and polycythemia. Alternatively, it could contribute to the management of metabolic diseases associated with iron overload. This study aims to determine whether phlebotomy can improve insulin resistance and lipid profile in individuals with hyperferritinemia-related metabolic disorders.</p> Methods <p>Publications in Cochrane Library, MEDLINE (PubMed), CINAHL (EBSCO), Academic Search Ultimate, and Web of Science were searched up to the 15th of December 2025. Search was limited to English- and Spanish-language publications. Funnel plots were calculated for each main outcome to assess potential publication bias, and the risk of bias in individual studies was evaluated using the RoB 2 and ROBINS-I tools. Standard mean differences (SMDs) and 95% CIs between individuals phlebotomized and controls were used to calculate the effect size using a random-effects model. Meta-regression assessed whether baseline ferritin levels and phlebotomy-induced reductions in ferritin correlated with improvements in insulin resistance and lipid profile.</p> Results <p>Twelve studies were eligible for analysis, comprising 549 phlebotomized and 571 control subjects. Phlebotomy was associated with a small but significant improvement in insulin resistance (SMD −0.33; CI −0.56 to −0.10; <i>p</i> = 0.006; I² = 70%) and a borderline improvement in blood triglycerides (SMD −0.12; CI −0.25 to −0.001; <i>p</i> = 0.05; I² = 3%), but did not improve total cholesterol (SMD −0.10; CI −0.33 to 0.12; <i>p</i> = 0.36; I² = 50%). No significant associations were found between baseline ferritin levels or post-phlebotomy ferritin reduction and insulin resistance. However, ferritin reductions correlated with reductions in triglyceride levels after phlebotomy.</p> Conclusion <p>The findings highlight the potential of phlebotomy as an adjuvant therapy to improve insulin resistance, independent of baseline ferritin levels. Given that phlebotomy is a safe, well-tolerated, and low-cost procedure, it could lead to increased blood donation rates, which in turn could impact nursing practice, as nurses are the primary healthcare professionals involved in this clinical procedure.</p> Meta-analysis registration <p>This meta-analysis was registered in the Prospective International Register of Systematic Reviews (PROSPERO) ID: CRD42024522931.</p>