Objective: The current study aimed to investigate and compare the efficiency of the total extract and ethyl acetate (EtOAc) extract of Mangifera indica leaves to attenuate iron overload-induced hepatic and splenic dysfunctions, using an in-vivo iron-overload rat model. Methods: Rats received water supplemented with iron for 2 months, followed by treatment with either total extract or EtOAc extract of M. indica leaves for an extra 2 months. Results: Rats treated with EtOAc fraction of M. indica leaves, and the total extract, had significantly diminished iron accumulation within hepatic and splenic tissues. Both extracts normalized the hepatic enzymatic and non-enzymatic biomarkers like alkaline phosphatase (ALP), alanine aminotransferase (AST), and total bilirubin. Moreover, they restored the oxidants/antioxidants balance within the liver and spleen tissues. Additionally, they suppressed HO-1 levels, increased Nrf2 expression, and downregulated MMP-9 expression. Conclusion: Briefly, M. indica extracts showed iron-chelation, antioxidant, and antifibrotic potentials. These findings pointed out the usefulness of the mango leaves as a natural, affordable by-product in managing iron overload complications. However, the results also demonstrated that EtOAc extract is more accountable for such activities.