The combined use of natural antibacterial bioactives offers enhanced antibacterial efficacy through complementary mechanisms; however, substantial differences in their physicochemical properties pose challenges to stable co-encapsulation and controlled release. To address this challenge, berberine (BBR) and quercetin (Que) were selected as model bioactives and co-encapsulated in hybrid vesicles (LZSF) co-assembled from Zein, silk fibroin (SF), and lecithins. The co-loaded vesicles were further confined within a dynamic hydrogel network formed by oxidized hyaluronic acid (OHA), carboxymethyl chitosan (CMC), and gelatin (Gel) through Schiff-base reactions, thereby constructing a pH-responsive composite hydrogel. The co-loaded hybrid vesicles exhibited particle sizes ranging from 117.85 to 145.23 nm, with encapsulation efficiencies of over 80% for both BBR and Que at suitable BBR/Que mass ratios, demonstrating effective co-encapsulation. FTIR spectroscopy, rheological measurements, and SEM observations indicated the formation of a stable dynamically crosslinked network, in which the hybrid vesicles were uniformly distributed. The hydrogel with a CMC/Gel mass ratio of 2:1 exhibited favorable network characteristics. In vitro release studies showed that the 24 h cumulative release of both BBR and Que at pH 5.5 was significantly higher than that at pH 7.4, demonstrating pronounced acid-responsive release behavior. The optimized composite hydrogel exhibited strong antibacterial activity against Cutibacterium acnes, with an inhibition zone diameter of 24.24 mm. Overall, the integration of lecithins–protein hybrid vesicle-mediated co-encapsulation with dynamic hydrogel confinement enabled efficient co-loading, spatial confinement, and pH-responsive release of natural bioactives with distinct polarities, providing a promising strategy for the application of natural antibacterial bioactives in functional foods and food preservation.