In the current study, we found that WDFY3‐AS2 down‐regulation promoted cell proliferation and invasion, whereas WDFY3‐AS2 up‐regulation markedly suppressed cell proliferation and invasion in ESCC EC9706 and TE1 cells, coupled with EMT phenotype alterations, implying targeting WDFY3‐AS2 may be a novel therapeutic strategy for ESCC patients. The gene discussed is WDFY3; the disease is esophageal squamous cell carcinoma.