In this study, prepared acetylated bovine whey (ABW) was tested as a highly efficient hepatoprotective agent like that of the old drug N-acetyl cysteine (NAC) against the induction of iron overloading (IO) in a rat model. The probably prophylacting antioxdative characteristic features that were prominently executed on tissue content of reactive oxygen species (ROS), antioxidative ferritin, and proinflammatory IL-6 via the enhanced tissue protecting Nf-E2-related factor 2 (Nrf2) pathway. The reduction in macrophagic M2 CD163 and Kupffer M1 CD68 as well as apoptotic caspase 3 distribution denoted the efficacy of the targeting cellular prophylacting activity. In addition, the reduced abnormalities in the hepatocellular nuclei, cytoplasmic reticulum, mitochondrial degeneration as well as granular glycoproteins, and secondary lysosomal appearance promoted the more preferable usage of the natural product whey supplement than the risky NAC in IO cases.