Quantum dot-doped mesoporous microbeads (QDMMs) are encapsulated with silica shells for enhanced chemical stability. The results show that a microemulsion procedure is highly efficient in coating QDMMs with polyvinyl alcohol (PVA), which is important in the subsequent deposition of a silica shell. Incorporation of fluorescent silane precursors allows direct observation of silica shells by fluorescence microscopy. The resulting silica-coated QDMMs (QDMM@SiO2) exhibit remarkable stability against solvent-induced QD leaching and chemical-induced fluorescence quenching compared with the uncoated QDMMs. Further development of this technology such as optimization of silica shell thickness, surface modification with non-fouling polymers, and conjugation with biomolecular probes will enable clinical translation of the optical barcoding technology for highly multiplexed detection and screening of genes and proteins.