Objective To investigate the effect of desmoglein 2 (DSG2) knockdown on proliferation, invasion, migration, and epithelial⁃mesenchymal transition (EMT) of nasopharyngeal carcinoma cells. Methods Nasopharyngeal carcinoma CNE‑2R cells and normal nasopharyngeal epithelial NP69 cells were routinely cultured. CNE‑2R cells were divided into negative control group (NC group, transfected with empty vector lentivirus) and DSG2‑silenced group (shDSG2 group, transfected with DSG2‑silenced lentivirus). RT‑qPCR and Western blot were used to detect DSG2 mRNA and protein expressions in CNE‑2R cells, NP69 cells, and CNE‑2R cells from the NC and shDSG2 groups. CNE⁃2R cells proliferation, colony formation, proliferation rate, migration, and invasion were detected and compared between the NC and shDSG2 groups using cell proliferation‑toxicity assay, plate colony formation assay, EdU assay, wound healing assay, and Transwell assay, respectively. Western blot was performed to detect and compare the expressions of β‑catenin, E‑cadherin, N‑cadherin, and vimentin in CNE‑2R cells between the two groups. Results DSG2 mRNA and protein expressions were elevated in CNE‑2R cells than in NP69 cells (P<0.05). Compared with the NC group, the shDSG2 group showed reduced DSG2 mRNA and protein expressions in CNE⁃2R cells (P<0.05). On days 2, 3, 4, and 5 of the intervention, the OD values of CNE‑2R cells in the shDSG2 group were lower than those in the NC group (P<0.05). The proliferation rate, migration rate, number of colony‑forming units, and numbers of migrating and invading cells of CNE‑2R cells were lower or less in the shDSG2 group compared with the NC group (P<0.05). Relative to the NC group, the shDSG2 group exhibited increased E‑cadherin expression and decreased expressions of β‑catenin, N‑cadherin, and vimentin in CNE⁃2R cells (P<0.05). Conclusion DSG2 is highly expressed in nasopharygeal carcinoma CNE‑2R cells. Silencing DSG2 suppresses the proliferation, migration, and invasion of CNE‑2R cells and inhibits the EMT process.