Several potential health hazards are associated with the wide use of titanium dioxide nanoparticles (e.g., n-TiO2). The primary aim of the current study was to detect the toxic effects of 800 mg/kg 50 nm n-TiO2 on bone metabolism. Comparative studies were conducted to determine whether natural antioxidants, such as idebenone, carnosine and melatonin, could ameliorate the hazardous effects of n-TiO2 on down regulation of bone. The results of this study revealed that n-TiO2 treatment produced bone complications, which were confirmed by alteration of serum tumor necrosis factor-α (TNF-α, inflammatory cytokine) level and bone alkaline phosphatase (B-ALP; bone formation marker), and C-terminal peptide of type I collagen (CTx; bone resorption marker) in treated rats compared with controls. The administration of the previously mentioned antioxidants along with n-TiO2 treatment significantly modulated the alterations in most the inflammatory cytokines and biomarkers. It was concluded that treatment with idebenone, carnosine and melatonin protects against n-TiO2 oxidative stress-induced bone complications.