Zeolitic imidazolate framework-8 (ZIF-8) is one type of metal-organic framework (MOF) with excellent thermal and solvent stability and has been used extensively in separation, catalysis, and gas storage. Supported ZIF-8 structures can offer additional advantages beyond the MOF-only materials. Here, spheres-on-spheres (SOS) silica microspheres are used as support for the nucleation and growth of ZIF-8 nanocrystals. The surface functionalities (-SH, -COOH, and -NH2) of silica and reaction conditions are investigated for their effects on the ZIF-8 morphology. The use of SOS microspheres results in the formation of highly crystalline ZIF-8 nanostructured shell with varied sizes and shapes, ranging from spherical to cubic and to needle crystals. The SOS@ZIF-8 microspheres are packed into a column and utilized for separation of aromatic molecules on the basis of π-π interaction in high-performance liquid chromatography (HPLC). Furthermore, by thermal treatment in air, ZIF-8 nanocrystals can be transformed into ZnO coating on SOS silica microspheres. The SOS@ZnO microspheres show excellent photocatalytic activity, as measured by degradation of methyl orange in water, when compared to ZnO nanoparticles. This study has demonstrated the facile way of using SOS microspheres to prepare core-shell microspheres and their applications.