Nanoparticles enter into the digestive tract will quickly adsorb the protein-based biomacromolecules and form protein coronas, which can affect the release characteristic of the encapsulated bioactive compounds. In this study, edible dock protein (EDP) nanoparticles were chosen as the model nanoparticles, and quercetin (Que) was chosen as the representative bioactive compound, the regulatory mechanism of protein coronas on the release characteristic of Que within the EDP nanoparticles was investigated. Results showed that the digestive enzymes can adsorb on the surface of the Que-EDP nanoparticles and form protein coronas during the simulated digestion. Herein, hydrogen bonding, van der Waals force, and hydrophobic interactions were the main adsorption forces between digestive enzymes and nanoparticles. Moreover, the protein coronas formed by α-amylase, pepsin, trypsin, and amylopsin increased the zeta potential of the Que-EDP nanoparticles from −17.9 mV to −11.2 mV, +3.8 mV to +7.0 mV, −21.9 mV to −19.2 mV, and −21.9 mV to −12.1 mV, respectively. The particle size, polydispersity index, and protein conformation of the nanoparticles were also remarkably changed after the formation of protein coronas. Besides, the activity of α-amylase and amylopsin on the surface of the Que-EDP nanoparticles was enhanced by 1.4 and 1.6 times. The simulated digestion experiments indicated that α-amylase and amylopsin coronas slowed the release of Que, while pepsin and trypsin coronas accelerated the release of Que. This study will provide a new idea and theoretical basis for the rational design of nanoparticle carriers.