Girdin is an actin-binding Akt substrate that is involved in the regulation of cell migration. Accumulating evidence has revealed that girdin has regulatory effects on invasion and metastasis in several types of cancer. However, the role of girdin in esophageal squamous cell carcinomas (ESCCs) is yet to be investigated. In the present study, tissue microarray data revealed that among 95 cases of ESCC, 27 cases (28.7%) exhibited a low expression of girdin, while 67 cases (71.3%) had an enhanced expression of girdin. However, among 78 cases of adjacent tissues, 64 cases (82.1%) did not express girdin and 14 cases (17.9%) exhibited a low expression of girdin. Furthermore, the expression of girdin was significantly associated with the tumor stage, lymph node metastasis stage, and tumor, lymph node and metastasis stage. Of note, the mean survival time of girdin-positive cases was only 30.62±2.99 months, while it was 53.37±5.02 months in girdin-negative cases, indicating that girdin protein expression is an independent prognostic factor of poor survival. Talen-mediated girdin knockout (KO) significantly suppressed cellular proliferation, migration and invasion in ESCC ECA109 cells. In conclusion, the present study suggested that girdin protein expression was significantly correlated with cancer progression and poor prognosis in ESCCs, and that girdin had a positive role in the regulation of cell proliferation, migration and invasion in ESCC cells. Therefore, girdin may be a potential candidate for the development of novel prognostic tools and therapeutic strategies for ESCCs.