In this study we formed and characterized dynamic hydrogel microspheres in which a protein conformational change was used to control microsphere volume changes and the release of an encapsulated drug. In particular, a specific biochemical ligand, trifluoperazine, induced calmodulin's nanometer scale conformation change, which translated to a 48.7% microsphere volume decrease. This specific, ligand‐induced volume change triggered the release of a model drug, vascular endothelial growth factor (VEGF), at pre‐determined times. After release from the microspheres, 85.6 ± 10.5% of VEGF was in its native conformation. Taken together, these results suggest that protein conformational change could serve as a useful mechanism to control drug release from dynamic hydrogels.magnified image