Background: The Wnt/\beta-catenin signaling pathway plays crucial roles in tumor budding and the epithelial–mesenchymal transition (EMT). Myeloid ecotropic viral insertion site 3 (MEIS3)—a direct target of Wnt/\beta-catenin—promotes vagal neural crest cell migration into the gut tissue during development; however, its role in cancer progression remains unclear. In this study, the role of MEIS3 in colorectal cancer (CRC) progression was investigated. Methods: We analyzed the association between MEIS3 protein expression and the clinical stages of CRC patients, and the effect on tumor cell migration and invasion by wound healing and transwell assays. Finally, we analyzed the association between MEIS3 expression and the disease-free survival (DFS) and overall survival of CRC patients through Kaplan–Meier analysis. Results: We found that MEIS3 expression was strongly associated with CRC progression and could be employed to assess DFS in postoperative patients. MEIS3-positive cells were mainly distributed in the growth front and tumor–stroma interface of the CRC tissues, which contain abundant EMT-active and tumor budding cells dominating cancer metastasis. Moreover, MEIS3 promoted CRC cell migration and invasion by regulating effectors including laminin subunit beta 1, matrix metalloprotein 2, and vimentin. MEIS3 protein expression increased with CRC progression according to the clinical stage, which could be used as a biomarker to stratify CRC patients. The 5-year DFS of MEIS3-high patients was poorer than that of MEIS3-low patients (40.6% vs. 61.7%; p 0.0001). Moreover, the 5-year DFS of stage II patients with MEIS3-high expression (53.4%) was comparable to that of stage III patients with MEIS3-low expression (49.5%), while the 5-year DFS of MEIS3-high patients in stage III (30.9%) was comparable to that of stage IV patients (29.6%). Conclusions: This study showed that MEIS3 can promote cancer cell metastasis and thus may be a promising biomarker for higher rates of recurrence in postoperative patients with stage II/III CRC.