Mesoderm induction early response 1, family member 3 (MIER3) has recently been identified as a potential cancer susceptibility gene. However, the expression pattern and the role of MIER3 in the progression of colorectal cancer (CRC) have not yet been well characterized. Here, we reported that MIER3 was significantly reduced in human primary colorectal cancer and was associated with CRC metastasis and poor prognosis. Moreover, the up-regulation of MIER3 expression significantly inhibited CRC cell proliferation, migration and invasion in vitro and repressed tumor growth and metastasis in vivo. In contrast, down-regulation of MIER3 could promote the aggressive behaviors of CRC cells. Furthermore, our study showed that MIER3 inhibited cell proliferation and invasion partially via reduction of Sp1 and subsequent suppression of epithelial-mesenchymal transition (EMT). In conclusion, our data suggested that MIER3 plays a potential tumor suppressor role in CRC progression and may be a potentially valuable clinical prognostic marker of this disease.