Abstract Oral ulcers are complex mucosal lesions characterized by infection, inflammatory imbalance, elevated oxidative stress and impaired vascular regeneration, with therapeutic efficacy hindered by rapid drug loss in the highly wet and dynamic oral environment. Here, we developed a Janus-structured bacterial cellulose (BC)-based multifunctional oral patch (Ber@ZIF/BC, BZB) for stable retention and controlled release of Ber@ZIF (BZ) at ulcer sites. Encapsulation of berberine within ZIF and incorporation into Janus BC endowed the system with robust wet adhesion and microenvironment-responsive drug release. In vitro, BZB effectively inhibited Staphylococcus aureus and Escherichia coli, scavenged intracellular reactive oxygen species, preserved cell viability under oxidative stress and promoted epithelial and endothelial cell migration and angiogenesis while modulating inflammatory cytokine expression. In rat oral ulcer models, BZB accelerated ulcer closure, enhanced collagen remodeling and neovascularization and restored the inflammatory microenvironment. This Janus BZB patch synergistically regulates infection, oxidative stress and tissue regeneration, offering a promising strategy for precise, durable and efficient treatment of oral ulcers with translational potential.