Iron accumulation in the brain causes oxidative stress, blood–brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron‐induced hippocampal damage compared to N‐acetyl cysteine (NAC). This 5‐week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme‐linked immunosorbent assay, spectrophotometry, and qRT‐ PCR were used to measure MMP‐9, tissue inhibitor metalloproteinase‐1 (TIMP‐1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2‐related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP‐9, TIMP‐1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO‐1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload‐induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.