This study demonstrates that Nogo-B promotes atrial fibrillation (AF) progression by reshaping the inflammatory microenvironment of epicardial adipose tissue (EAT). Integrated metabolomic and proteomic analyses revealed increased EAT whitening and elevated Nogo-B expression in AF patients. In vitro and in vivo experiments showed that Nogo-B drives preadipocyte differentiation into white-like adipocytes through the AKT2–GSK3β–β-catenin pathway, enhancing inflammation, atrial fibrosis, and arrhythmogenesis. Co-culture models further confirmed indirect adverse effects on cardiomyocytes and fibroblasts. Pharmacological activation of β-catenin signaling partially reversed these pathological changes, suggesting Nogo-B as a potential therapeutic target for AF.