45S5 Bioglass® (45S5 BG) is a frequently applied Type A bioactive material, capable of forming an inherent bond to bone and soft tissue. Currently, applied melt-derived bioactive glass powders (BG) exhibit particle sizes between a few to several hundred micrometers. Recent studies on nanometer-sized bioactive glasses (nBGs), produced by bottom-up methods like sol–gel processing or flame spray pyrolysis, have indicated their great potential for several biomedical applications. In this study, the feasibility of top-down processing starting from bulk 45S5 BG by wet comminution in a stirred media mill was investigated. The products were assessed by in vitro hydroxycarbonate apatite (HCAp) formation in simulated body fluid, which is a marker for bioactive behavior. The study reveals the paramount influence of the used solvent for a successful top-down processing: In comparison with the as-received material bioactivity is lost for powders processed in water, preserved for comminution in ethanol and increased for powders processed using the alcohols n-butanol, n-pentanol, and n-hexanol. It was also found that only for the latter solvents, the chemical composition of the glass is maintained during comminution. Flake-like, slightly porous particles with specific surface areas of ~25–30 m2/g are obtained. Thus, the presented comminution approach offers a convenient technique to process 45S5 BG with enhanced bioactivity.