Gastric cancer (GC) is one of the most common types of cancer worldwide, and it involves extensive local tumour invasion, metastasis and poor prognosis. Understanding the mechanisms regulating the progression of GC is necessary for the development of effective therapeutic strategies. Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is an important regulator controlling gene activation and repression, which has been thought to be involved in tumorigenesis. However, the role of TBL1XR1 in human GC remains largely unknown. Here, we find that TBL1XR1 is aberrantly expressed in human GC tissues, and TBL1XR1 levels are highly correlated with local tumour invasion, late tumor, lymph node, metastasis (TNM) stage and poor prognosis. Knockdown of TBL1XR1 by shRNA inhibits GC cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) in vitro, as well as tumorigenesis and peritoneal metastasis in vivo, whereas overexpression of TBL1XR1 produces the opposite effects. These effects are mediated by activation of the ERK1/2 signalling pathway, and inhibition of this pathway with a specific ERK1/2 inhibitor (U0126) significantly impairs the tumour-promoting effects induced by TBL1XR1. Moreover, TBL1XR1 mediated ERK1/2 activation is dependent on the β-catenin/MMP7/EGFR signalling pathway. In conclusion, TBL1XR1 contributes to GC tumorigenesis and progression through the activation of the β-catenin/MMP7/EGFR/ERK signalling pathway and may act as a new therapeutic target for GC.