Previous studies revealed that Asporin (ASPN) is a potential mediator in the development of various types of cancer as a secreted stroma protein, but the function of ASPN inside the cancer cells remains largely unknown. Here, we demonstrated a higher expression level of ASPN in colorectal cancer (CRC) than matched normal tissues, and 25% (2/8) CRC showed copy number variation (CNV) gain/amplification in ASPN gene. Both higher ASPN expression levels and ASPN CNV gain/amplification indicated a worse prognosis in CRC patients. ASPN can promote proliferation, migration, and invasion of CRC cells, and inhibit apoptosis by activating Akt/Erk and TGF-β/Smad2/3 signalings. Further investigations revealed that ASPN interacts with Smad2/3, facilitates its translocation into nucleus, and up-regulates the expression of Epithelial-mesenchymal transition (EMT) related genes. Rescue assays confirmed that TGF-β signaling is essential for the effects of ASPN on promoting CRC cell migration and invasion. In conclusion, ASPN promotes the migration and invasion of CRC cells via TGF-β/Smad2/3 pathway and could serve as a potential prognostic biomarker in CRC patients.