BACKGROUND: Blood transfusions are associated with increased morbidity and mortality, and maintaining global blood supplies can be a challenge. This systematic review investigates the impact of preoperative iron supplementation on the risk of blood transfusion among non-anemic patients undergoing major surgeries. METHODS: We conducted a systematic search of PubMed, Embase, and Cochrane Central for randomized controlled trials published up to May 2024. Studies involving the use of erythropoietin, or patients already using iron supplementation when trial randomization was conducted were excluded. Outcomes assessed included the number of individuals who received blood transfusions, and mean hemoglobin levels at the first day and by the first postoperative week. RESULTS: A total of 1,162 non-anemic patients from 9 studies were included. Of these, 54% received preoperative iron supplementation. The average age was 71 years, and 44% were women. Preoperative iron supplementation was associated with a significantly lower risk of receiving a blood transfusion (OR = 0.54; 95% CI 0.40 to 0.75; p < 0.001). At the first postoperative day, the iron supplementation group had significantly higher mean hemoglobin levels compared to the no-treatment group (MD = 0.22 g.dL-1; 95% CI 0.02 to 0.42; p = 0.03). However, the pooled results could not rule out the null hypothesis for the difference in mean hemoglobin levels throughout the first week (MD = 0.12 g.dL-1; 95% CI -0.12 to 0.35; p = 0.34). CONCLUSION: Preoperative intravenous iron supplementation in non-anemic patients undergoing major surgeries, particularly cardiac procedures, significantly reduces transfusion requirements. However, the benefits of oral iron remain uncertain, and further research is warranted to establish standardized perioperative supplementation protocols. PROSPERO IDENTIFIER: CRD42024552559.