Hydroxyapatite nanoparticles are regarded as an inorganic constituent found in natural bone and are primarily employed in tissue engineering because of their exceptional biocompatibility and bioactivity. Nevertheless, it remains uncertain whether they are safe for medical applications owing to their petite nano-scale particle size. From the previous studies, there was not enough data on nephrotoxicity and molecular changes induced by (high or low HAP-NPs) and the protection role of nano-antioxidants (CurNPs) in minimizing their toxicity. Therefore, the present study aimed to investigate the effect of high and low doses of HAP-NPs on the kidney system in male rats. At the molecular level, these results presented that the gene expression level, high HAP-NPs alone caused a significant increase in both kidney Injury Molecule-1 (KIM-1) and Lipocalin-2 (LCN-2) genes also, caused a significant increase in oxidative DNA damage (8-OHdG). The presence of Curcumin nanoparticles minimized the toxicity of high or low HAP-NPs due to their antioxidant properties and scavenging abilities against active free radicals.