BACKGROUND: The high metastasis rate is the primary contributor to the high mortality rate associated with muscle-invasive bladder cancer (MIBC). Therefore, elucidating the mechanisms involved and identifying potential therapeutic targets are crucial for improving the overall prognosis of bladder cancer (BLCA). METHODS: We used consensus clustering and differential gene expression analyses to identify the key gene desmoglein 3 (DSG3). Subsequently, we examined the expression of DSG3 in BLCA and its association with the clinical characteristics and prognosis. Comprehensive in vitro and in vivo experiments were conducted to elucidate the functions of DSG3 and the reasons behind the upregulation of DSG3 in BLCA, as well as to investigate the mechanisms by which DSG3 promotes metastasis. RESULTS: DSG3 was markedly upregulated in BLCA, particularly in the basal/squamous (Ba/Sq) subtype. Importantly, elevated DSG3 levels demonstrated a strong association with aggressive tumor behavior and poorer clinical outcomes. Functional experiments revealed that DSG3 knockdown significantly impeded cancer stemness characteristics, epithelial-mesenchymal transition (EMT), migration, and invasion capabilities in vitro, whereas in vivo studies showed marked reductions in tumorigenesis and lung metastasis. Mechanistic investigations indicated that STAT3 transcriptionally activated DSG3 expression in BLCA cells. Downstream pathway analysis further showed that DSG3 promoted AKT phosphorylation, thereby inhibiting GSK3β activity. This molecular pathway promoted β-catenin nuclear translocation, thereby triggering transcriptional upregulation of SOX2 and MMP7 expression, ultimately mediating BLCA progression. CONCLUSION: Our study demonstrates a novel mechanism by which DSG3 enhances cancer stemness, EMT, migration, and invasive capabilities through upregulation of SOX2 and MMP7 expression through the AKT/GSK3β/β-catenin pathway, ultimately leading to growth and metastasis of BLCA. This study elucidated the role of DSG3 in BLCA and its mechanism in activating the Wnt/β-catenin signaling pathway. We anticipate this study will identify potential biomarkers for predicting progression and for assessing prognosis. Furthermore, this study introduced a novel intervention target for BLCA treatment.