Many people suffer from bone-related diseases such as osteoporosis, osteosarcoma, microbial infections and cancer throughout the world each year resulting in their deaths. Recently, hydroxyapatite nanoparticles have been emerged as a potent nanotechnology-based delivery system to treat several diseases. Owing to their nanosizes (<100 nm), high surface to volume ratio, easy of surface functionalization and suitable physico-chemical features such as bioactivity, biocompatibility, osteoinductivity and osteoconductivity, they are highly potent and favorable to generate cytotoxicity to kill the cells especially by the high uptake of calcium concentration within the cells. Moreover, their appropriate surface-modifications with ligands and other biomolecules may make them highly efficient carrier to deliver potent loaded-cargos to specific site of interest with a controllable and sustained manner leading to cellular destructions. The review demonstrates their synthesis, surface-functionalizations, mechanism of actions, immune responses and biomedical applications against various diseases to consider them as future nanotechnological delivery system.