In this study, we produced a novel microsphere with a hybridized composition of gelatin and siloxane which is bioactive and degradable for the applications in bone regeneration fields. A solution of gelatin organic and siloxane inorganic containing calcium chloride was formulated into microspheres in an oil bath mediated by a surfactant. Following the processes of hydration, gelation and solidification, well-shaped spherical particles were produced with sizes of a few to hundreds of micrometers (68 μm on average). The obtained microspheres were highly stable in an aqueous solution due to the in situ cross-linking of the siloxane with gelatin chains, which eliminated the additional cross-linking step generally used in pure gelatin. The hybridized microspheres exhibited rapid induction of apatite-like crystals on their surface with incubation in a simulated body fluid, suggesting an excellent bone bioactivity in vitro. It is considered that the newly developed organic–inorganic microspheres may be useful for the regeneration of skeletal defects.