The efficacy of deferiprone (DFP) in reducing liver iron content is still inadequate. Ethanolic extract of Phaleria macrocarpa L. (PM) fruit showed iron chelation activity and hepatoprotective effects. This study aimed to evaluate the efficacy of the combination of deferiprone and PM extract to reduce iron content in the liver. Rats were divided into 6 groups: normal, iron overload (IO), IO+D-FP, IO+PM extract, IO+PM+DFP normal, or half dose. Rats were induced with iron-dextran injections over 8 weeks, with therapy starting from week 4. Measurements included hepatic iron, malondialdehyde (MDA), GSH, and TNF-α levels, hepatic GPx4 mRNA expression, plasma ALT and AST activity, and histopathology. While none of the treatments significantly reduced hepatic iron, treatment with PM+DFP half dose showed the greatest reduction and improved MDA, ALT, AST, and TNF-α levels compared to DFP monotherapy. GSH and GPx4 mRNA were not significantly altered by the combination therapy. © (2024), (Pensoft Publishers). All rights reserved.