Background <p>Anterior gradient 2 protein (AGR2) is associated with tumorigenesis and metastasis in different cancers. However, its role in nasopharyngeal carcinoma (NPC) remains unknown. This study aimed to explore the effect of AGR2 on epithelial-mesenchymal transition (EMT) in NPC and its underlying mechanisms.</p> Methods <p>AGR2 expression was analyzed in cancerous and para-cancerous tissues from ten NPC patients using RT-qPCR. Western blotting was used to determine the AGR2 protein levels in two NPC cell lines and a nasopharyngeal epithelial cell line. AGR2 was overexpressed or knocked out in NPC cells and its effects on cell viability, migration, invasion, and EMT markers were evaluated in vitro.</p> Result <p>AGR2 expression was significantly higher in NPC tissues compared to adjacent normal tissues. Similarly, NPC cell lines exhibited increased AGR2 levels compared to the nasopharyngeal epithelial cell line. AGR2 knockout significantly reduced cell viability, migration, and invasion. It also decreased N-cadherin protein levels while increasing E-cadherin, α-SMA, and vimentin expression. Conversely, AGR2 overexpression produced the opposite effects. Furthermore, AGR2 deletion inactivated the TGF-β/Smad signaling pathway.</p> Conclusion <p>AGR2 promotes tumor progression and EMT in NPC through activation of the TGF-β/Smad signaling pathway. These findings suggest that AGR2 may serve as a potential biomarker and therapeutic target for NPC.</p>