Mesoporous silica has received considerable attention as a drug delivery vehicle because of its large surface area and large pore volume for loading drugs and large biomolecules. Recently, mesoporous silica microparticles have shown potential as a three-dimensional vaccine platform for modulating dendritic cells via spontaneous assembly of microparticles in a specific region after subcutaneous injection. For further in vivo applications, the biodegradation behavior of mesoporous silica microparticles must be studied and known. Until now, most biodegradation studies have focused on mesoporous silica nanoparticles (MSNs); here, we report the biodegradation of hexagonally ordered mesoporous silica, SBA-15, with micrometer-sized lengths (∼32 μm with a high aspect ratio). The degradation of SBA-15 microparticles was investigated in simulated body fluid (SBF) and in mice by analyzing the structural change over time. SBA-15 microparticles were found to degrade in SBF and in vivo. The erosion of SBA-15 under biological conditions led to a loss of the hysteresis loop in the nitrogen adsorption/desorption isotherm and fingerprint peaks in small-angle X-ray scattering, specifically indicating a degradation of ordered mesoporous structure. Via comparison to previous results of degradation of MSNs in SBF, SBA-15 microparticles degraded faster than MCM-41 nanoparticles presumably because SBA-15 microparticles have a pore size (∼8 nm) and a pore volume larger than those of MCM-41 mesoporous silica. The surface functional groups, the residual amounts of organic templates, and the hydrothermal treatment during the synthesis could affect the rate of degradation of SBA-15. In in vivo testing, previous studies focused on the evaluation of toxicity of mesoporous silica particles in various organs. In contrast, we studied the change in the physical properties of SBA-15 microparticles depending on the duration after subcutaneous injection. The pristine SBA-15 microparticles injected into mice subcutaneously slowly degraded over time and lost ordered structure after 3 days. These findings represent the possible in vivo use of microsized mesoporous silica for drug delivery or vaccine platform after local injection.