Iron oxide nanoparticles (IONPS) have different practical purposes in nanomedicine. These new applications of IONPS have raised risk of exposure of this nanomaterials to humans. Up to the present, all features of IONPS toxicity are not fully characterized after exposure to animals. The aim of the present study is to investigate the acute toxicity effects of IONPS in laboratory animals regarding pathotoxicological analysis and clinical aspects. Twenty four male Wistar rats were selected, and separated into four groups. The first, second, and the third groups received 50, 500, and 5000 mg/kg of IONPS solution orally for five days through gavage, respectively. Animal mortality, clinical sings and body weight were evaluated during the study. Fourteen days after the last administration, rats were euthanized for further investigation for histopathological evaluation. There were no death observed in all groups. High and middle dose of the IONPS caused symptoms like lethargy, ataxia, anorexia, isolation, and respiratory arrhythmia over the period of the study. The subjects of the low dose group showed no signs of toxicity. Specific histopathological complications, like hyaline cast in the kidneys, hyperemia and interstitial thickening in the lungs, hemorrhage in the heart and hepatic degeneration in the liver were observed in high dose group. Thus, it can be concluded that, toxicity of IONPS in rats is dose-dependent. This particular size of IONPS can induce serious pathological abnormalities and clinical symptoms in high dose.