Abstract: This study aimed to investigate the structural changes of rice bran protein during gastrointestinal digestion and the immunomodulatory activity of its digestive products. Rice bran protein (RBP) was used as the raw material. Changes in molecular weight, microstructure, and amino acid composition were analyzed at different stages of in vitro simulated gastrointestinal digestion. The immunomodulatory activity of RBP digestion products (RBPI) was evaluated using RAW264.7 murine macrophage cells as a model. Most of the digestive products exhibited a molecular weight below 10 kDa after simulated gastrointestinal digestion. The β-sheet content increased from 33.66% to 46.50%, while the α-helix content decreased from 22.38% to 15.80%. Essential amino acids (EAA) accounted for 40.33% of the total amino acid content, with an EAA to non-essential amino acid (NEAA) ratio of 0.68. Digestion changed the microstructural of the protein, and the surface of the digestive products appeared finely granular. RBPI, at concentrations of 50~600 μg/mL, significantly enhanced the viability of RAW264.7 cells and notably increased their phagocytic capacity and nitric oxide production. Furthermore, RBPI significantly stimulated the secretion of the cytokines interleukin (IL)-1β, IL-10, and tumor necrosis factor-α (TNF-α) by macrophages, indicating strong immunoenhancing activity. These findings indicated that RBP, after in vitro simulated digestion, had good nutritional value and potential to activate macrophages and boost immune function, it was expected to provide data support for the application of gastrointestinal digestion products of rice bran protein in the functional food and health food industries.