Oral ulcers, the most common type of mucosal lesion, are both highly prevalent and prone to recurrence. In the persistently moist environment of the oral cavity, current therapeutic patches face challenges such as short adhesion time, disruption by food particles and bacteria, and oral movements. To address these challenges, we develop a Janus patch, named ANSB, inspired by the multi-layered and asymmetric structure of natural mucosa, featuring a long-lasting adhesive layer and a lubricating layer. By eliminating the salivary barrier and leveraging covalent crosslinking between tissue surface amine groups and N-hydroxysuccinimide ester (NHS), the adhesive layer-composed of gelatin and acrylic acid-achieves rapid (≤ 30 s), strong (≥ 45 kPa), and durable (≥ 8 h) adhesion to wet buccal tissues. Furthermore, the efficient lubricating effect (COF = 0.02 ± 0.003) provided by zwitterions renders the lubricating layer of ANSB highly similar to natural mucosal tissue, effectively preventing bacterial invasion, secondary damage, and unintended adhesion. Additionally, the strong interlayer bonding and complementary mechanical properties are confirmed, resulting in a unified performance characterized by rapid wet adhesion, hydration lubrication, and enhanced mechanical strength. Importantly, ANSB treatment demonstrates a long-term protective barrier and superior therapeutic effects in rat oral ulcers, inhibiting pseudomembrane formation and accelerating tissue regeneration without causing secondary damage. Consequently, this distinctive Janus patch, characterized by prolonged adhesion, efficient lubrication, and simple preparation, holds significant potential for clinical oral ulcer treatment. STATEMENT OF SIGNIFICANCE: Oral ulcers, with healing impeded by secondary injury and bacterial invasion due to the absence of protective barriers, are highly prevalent and recurrent. However, sustaining therapeutic materials and physical barriers in the highly dynamic and moist oral environment poses a considerable challenge. In this study, a Janus patch (ANSB) that integrated a soft wet adhesive layer and a tough lubricating layer was developed to reconstruct a new protective barrier thus preventing external stimuli such as secondary damage and bacterial infiltration. This innovative patch with high therapeutic potential for oral ulcers may offer a new way for ulcer treatment based on barrier protection.