Background: Phlebotomy has been used as a non-pharmacological treatment for different types of diseases, regarding the philosophy of humors in traditional medicines, such as Persian Medicine. However, according to the narrow-approved indications for phlebotomy in Western Medicine, we aimed to systematically summarize high-level of evidence on safety and efficacy of phlebotomy in treatment of human diseases., Methods: In this umbrella review, to identify meta-analysis studies of clinical trials on phlebotomy, four electronic databases, including PubMed, web of science, Scopus, and Cochran library were searched until Jun 18, 2022 with relevant keywords for 'phlebotomy' and 'meta-analysis' according to PRISMA guidelines and PICO questions. After excluding irrelevant studies, data on subject characteristics, method of intervention, and adverse events were extracted. To evaluate the quality of the methodology of the systematic reviews, AMSTAR2 scale was utilized., Results: From 327 identified studies, 7 full texts met the inclusion criteria, consisting of 56 clinical trials on 5648 subjects. These meta-analysis studies reported effects of phlebotomy on hypertension, acute gouty arthritis, skin disease (chronic urticaria and porphyria), and liver diseases (non-alcoholic fatty liver disease, chronic hepatitis C, and liver surgery). Our results showed significant improvements in different outcomes, while the most common adverse event was hematoma., Conclusion: The level of evidence on the efficacy and safety of phlebotomy in some specific health conditions was substantial; however, to investigate the efficacy and safety of phlebotomy in management of other health problems more clinical studies with high sample sizes are needed., (Copyright© 2024 Khatami et al. Published by Tehran University of Medical Sciences.)