Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial cancer of the esophageal epithelium. Piezo-type mechanosensitive ion channel component 1 (Piezo1), an essential mechanosensitive protein, plays an important role in maintaining cell biological functions under the stimulation of physiological force. Immunohistochemical and bioinformatic analyses of ESCC tissue samples indicate that Piezo1 expression is higher in ESCC tissues than in paracancerous tissues. shRNA-mediated Piezo1 downregulation in the ESCC lines EC9706 and EC109 showed that proliferation, migration, and invasion were suppressed by Piezo1 knockdown. Piezo1 downregulation suppresses ESCC migration and invasion in both cells and tissues via the epithelial–mesenchymal transition pathway. Moreover, G0/G1 to S-phase cell cycle progression was inhibited, and cell apoptosis was induced by Piezo1 downregulation. Furthermore, we observed an interaction between Piezo1 and p53 using immunoprecipitation. The protein levels of p53, downstream factor Bax, apoptosis executioner cleaved-caspase3, and caspase3 were significantly upregulated by the downregulation of Piezo1. The inhibited growth rate and upregulated expression of these related factors were validated using tumor-bearing mice. Therefore, Piezo1 downregulation induces ESCC apoptosis via a Piezo1–p53–Bax–Caspase 3 axis. In conclusion, Piezo1 downregulation suppresses ESCC development, and mechanosensitive protein Piezo1 can be considered a new target for ESCC therapy.