Background: Esophageal squamous cell carcinoma (ESCC) is a common cancer with poor prognosis. The molecular pathogenesis underlying ESCC remains to be explored. Leucine-rich alpha-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of various cancer types, however its role in ESCC is unknown. Materials and Methods: Data from the public database was analyzed to address the expression of LRG1 in ESCC. Gain-of-function studies were performed in select ESCC cell lines by over-expression or addition of recombinant LRG1, while loss-of-function studies achieved by small interfering RNA mediated knockdown. Wound healing and transwell assays were conducted to investigate ESCC cell migration and invasion upon manipulating LRG1 levels. Western blot and Immunofluorescence staining were used to examine the changes in epithelial to mesenchymal transition (EMT) and TGF beta signaling pathway. Results: LRG1 mRNA levels were found to be significantly down-regulated in patients with ESCC as well as in several ESCC cell lines. Silencing of LRG1 promoted, while overexpression of LRG1 inhibited ESCC cell migration and invasion. In line with this, Silencing of LRG1 enhanced, while overexpression of LRG1 reduced TGF beta signaling and EMT of ESCC cells. Conclusion/Significance: LRG1 suppresses ESCC cell migration and invasion via negative modulation of TGF beta signaling and EMT. Down-regulation of LRG1 in ESCC patients may favor tumor metastasis and disease progression.