Autofluorescent bovine serum albumin (BSA) hydrogel microspheres were prepared through the spray-drying of glutaraldehyde cross-linked BSA nanoparticles and then used for a proteinase K based degradation study in an aqueous solution. Experimental results and empirical models are presented to characterize the kinetics of BSA hydrogel microsphere degradation, as well as the accompanying release of synthesized fluorophore. The BSA gel degradation dynamics is primarily controlled by the concentration of proteinase K within the Tris buffer. The coupling of swelling dynamics and the transient distributions of fluorophore are traced by confocal microscopy. Models are developed based on the linear theory of elastic deformation coupled to enzyme and fluorophore transport. This study represents a fundamental investigation of the degradation and release kinetics of protein-based materials, which can potentially be applied for the dynamic and photostable tracking of relevant in vivo systems.