Hereditary anemia known as thalassemia requires regular blood transfusions leading to an increase in total iron levels which can be toxic due to the formation of free radicals that damage cells and tissues. Oxidative stress and inflammation caused by excess iron can lead to renal disease progression. Mangiferin, an active constituent in Phaleria macrocarpa (Scheff.) Boerl (PM) fruit, has been shown to be an iron chelating agent whose complexes can facilitate excretion and reduce iron accumulation. This study aims to determine the effectiveness of an ethanolic extract of PM fruit as an iron-chelating agent in a rat model of iron overload. Thirty Sprague-Dawley rats were divided randomly into six groups: normal (N), iron overload (IO), iron overload treated with 462.5 mg/kg deferiprone (IO+D), iron overload treated with 50 mg/kg mangiferin (IO+M), and iron overload treated with 100 mg/kg PM extract (IO+PM100) and 200 mg/kg PM extract (IO+PM200). Iron overload was established by injection administered twice per week for 3 weeks and was continued for 8 weeks with treatment. Kidney iron levels were measured using AAS. Plasma urea and creatinine, and renal TNF-α levels were measured using assay kits. Kidney mangiferin levels were measured using HPLC. Mangiferin and PM extract cannot significantly reduce plasma urea and kidney iron levels and their effect on plasma creatinine levels was nonlinear. However, mangiferin and PM extract can reduce renal TNF-α levels significantly. Mangiferin and PM fruit extract have iron chelator ability and reduce inflammatory responses caused by iron overload. © 2024 by Indonesian Journal of Pharmacy (IJP).