Although several studies highlight the important role of cAMP-responsive element binding protein (CREB) in tumor progression, little is known concerning the expression and function of CREB in esophageal cancer. In the present study, the expression of CREB was evaluated using a human esophageal squamous cell carcinoma tissue array by immunohistochemical analysis, which was confirmed by western blot analysis of tissues from esophageal cancer, and adjacent esophageal tissue. The role of CREB on esophageal cancer cell growth was analyzed in vitro and in vivo. Results showed that CREB was overexpressed in esophageal squamous cell carcinomas tissues, which was positively correlated with lymph node metastasis and tumor-node-metastasis (TNM) stage of esophageal cancer patients. Downregulating the expression of CREB effectively reduced esophageal cell growth in vitro and in vivo, induced S phase cell cycle arrest, triggered apoptosis and inhibited cell migration and invasion. These findings suggested CREB as an attractive drug target for esophageal cancer.