To improve the intestinal delivery of resveratrol, soy protein peptides (SPP) and transglutaminase (TGase) were used to prepare nanogels (NGs). The results demonstrated that, compared with native soy protein isolate (SPI) NG, SPP-NG showed a lower encapsulation efficiency (EE, 70.26%), a higher release efficiency (RE, 95.83%), and a smaller particle size (194.43 nm). However, the addition of TGase increased the EE and particle size to 74.37% and 217.73 nm, respectively. The RE of SPP-TGNG was also maintained at as high as 93.28%. Interestingly, SPP-TGNG exhibited optimal bile acid–binding capacity and cholesterol-lowering digests. The differences in delivery effects and morphology were attributed to structural changes in NGs. The unfolding and exposure of hydrophobic residues and weakened hydrogen bonds by hydrolysis resulted in a disordered and loose network structure, but it was beneficial to the production of cholesterol-lowering peptides and amino acids after digestion. The presence of TGase strengthened the crosslinking network by increasing β-sheet contents, hydrogen bonds, hydrophobic interactions, and isopeptide bonds. The alteration in multilevel structure would further affect the digestive products. The exposure of more hydrophobic residues and isopeptide crosslinking may be the intrinsic reason for the production of more hypocholesterolemic peptides and amino acids. This study indicated that the combination of hydrolysis and TGase treatment enhanced the delivery efficiency and bioactive properties of peptide-based NGs to resveratrol and revealed the internal mechanism between the structural changes and delivery efficiency. This work offers a theoretical foundation and technical suggestions for the production of peptide-based cargo systems and hydrophobic active substances.