Monodisperse microspheres of reconstituted silkworm cocoon silk were produced using a glass capillary-based microfluidic system and by identifying an appropriate solvent/nonsolvent fluid system. The microspheres can be produced to a range of different diameters depending on the system flow rates and have a nearly homogeneous size distribution. The silk microspheres exhibit a unique core-shell architecture and have a largely β-sheet structure, as measured by infrared spectroscopy. Mechanical characterization was performed with AFM nanoindentation and indicates that the microspheres are unexpectedly soft for a silk material. Because silk is well established as biocompatible and biodegradable, we anticipate that these silk microspheres could have particular utility in drug delivery and controlled release.