In the absence of any surfactants, organic solvent or template-directing reagents, the biomimetic hydroxyapatite porous microspheres with co-substituted essential trace elements (Na, Mg, K, F, Cl and CO₃²⁻) of natural bone was synthesized via a low-temperature hydrothermal method, using Ca(NO₃)₂ and NH₄H₂PO₄ as Ca and P sources, respectively; NaNO₃, Mg(NO₃)₂, KNO₃, NH₄Cl and NH₄F as substituted ion sources; and urea as the homogeneous precipitation reagent and CO₃²⁻ source. The synthetic powders were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), inductively coupled plasma atomic emission spectroscopy (ICP-AES) and ion chromatograph. The degradation, drug loading and release property of the synthetic materials were further investigated. The results showed that the synthetic biomimetic hydroxyapatite porous microspheres were constructed by two-dimensional nano-sheets with thickness of about 60 nm, and widths and lengths of up to 2 μm, and the selected area electron diffraction (SAED) pattern revealed that the nano-sheets in hydroxyapatite porous microspheres were single crystalline. The novel 3D architectures resulted in favourable drug loading and release properties, and the co-substituted essential trace elements enhanced the degradability of the porous microspheres in comparison with the traditional pure HAp materials.