More and more evidences show that TGF-β has a crucial role in tumor initiation and development. However, the mechanism of the TGF-β signal regulator in esophageal cancer (EC) is still unclear. Here, we use a variety of bioinformatics methods to analyze the expression and survival data of TGF-β signal regulators in patients with EC. We extracted the expression of the S-TGF-β signal regulator from The Cancer Genome Atlas (TCGA). The cBioPortal database was used to assess the frequency of genetic variation. The TGF-β signal regulator is expressed in EC and normal tissues. The objective is to use the Kaplan-Meier plotter database to investigate the prognostic value of TGF-β signal regulators in cancer patients. The DAVID and clusterProfiler software package were used for functional enrichment analysis. We found that patients with TGF-β signaling mutations have shorter overall survival, disease-free survival, disease-specific survival, platinum overall survival, and platinum-free progression survival. We found that compared with the noncancerous tissues of patients with EC, ZFYVE9, BMPR1B, TGFB3, TGFBRAP1, ACVRL1, TGFBR2, SMAD4, SMAD7, ACVR2A, BMPR1, and SMAD9 were significantly downregulated in tumor tissues, while ACVR1 and Smad1 were significantly upregulated in tumor samples. Univariate survival analysis showed that ACVR1, TGFBR3, TGFBRAP1, BMPR1A, SMAD4, and TGFBR2 were positively correlated with overall survival (OS) prolongation. In addition, TGF-β signal transduction regulators could be divided into two classes. Subclass 1 was involved in regulating cell adhesion, PI3K-Akt signaling, and Rap1 signaling. Subclass 2 was related to regulating angiogenesis and PI3K signaling. In short, all members of TGF-β signal regulators can be used as biomarkers to predict the prognosis of patients with EC.