G protein-coupled receptor 48 (GPR48) is an orphan receptor belonging to the G protein-coupled receptors (GPCRs) family, which plays an important role in the development of various organs and cancer development and progression such as gastric cancer and colorectal cancer. However, the prognostic value of GPR48 expression in patients with CRC has not been reported. In this study, we observed that GPR48 was overexpressed in primary CRC and metastatic lymph nodes, and closely correlated with tumor invasion and metastasis. Multivariate analysis indicated that high GPR48 expression was a poor prognostic factor for overall survival (OS) in CRC patients. In vitro and in vivo assays demonstrated that enforced expression of GPR48 contributed to enhance migration and invasion of cancer cells and tumor metastasis. In addition, we found that GPR48 increased nuclear beta-catenin accumulation, TCF4 transcription activity, and expression of its target genes including Cyclin D1 and c-Myc in CRC cells. Correlation analysis showed that GPR48 expression in CRC tissues was positively associated with beta-catenin expression. Up-regulation of GPR48 resulted in increased phosphorylation of GSK3beta, Akt, and ERK1/2 in CRC cells, while inhibition of PI3K/Akt and MAPK/ERK1/2 pathways was sufficient to abolish the effect of GPR48 on beta-catenin/TCF signaling. Taken together, GPR48 could serve as both a prognostic biomarker and a therapeutic target for resectable CRC patients.