To enhance the stability and bioavailability of blueberry anthocyanins (BA), this study constructed BA-loaded sodium alginate/chitosan/tannic acid hydrogels via an ion-induced pre-gelation technique and optimized their preparation parameters. Response surface methodology (RSM) indicated that the optimum conditions that provided maximum encapsulation efficiency (EE, 75.82%) were 1.13% sodium alginate, 0.49% tannic acid, and a BA concentration of 3.12 mg/mL. During in vitro simulated intestinal digestion, the cumulative release rate of free BA was only 53.58%, and after simulated intestinal digestion for 4 h, its 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) cation radical scavenging rates were (50.22 ± 2.00)% and (55.80 ± 3.44)%, respectively. Compared with free BA, the intestinal release rate of the BA-loaded hydrogel increased to 75.20%, and the DPPH radical and ABTS cation radical scavenging rates increased to (93.81 ± 1.83)% and (99.69 ± 0.28)%, respectively after 4 h of simulated intestinal digestion, indicating the targeted release and activity retention of encapsulated BA. In vitro colonic fermentation experiments demonstrated that compared with free BA, the hydrogel significantly lowered the Firmicutes/Bacteroidetes ratio and elevated the abundance of Proteobacteria to 17.02%, indicating an enhanced modulatory effect on the intestinal microbiota. Overall, this study offers a theoretical basis and technical support for the high-value application of BA in the food and health product industries.