Protein tyrosine phosphatase MEG2 (MEG2/PTPN9), a classic tyrosine-specific protein tyrosine phosphatase (PTP), is involved in the progression of liver, breast, and gastric cancers. However, the function and regulation of MEG2 in colorectal cancer (CRC) still remain unclear. In this study, we investigated the expression of MEG2 in CRC and found that MEG2 was downregulated in human CRC tissues compared to normal corresponding tissues. Moreover, in vivo and in vitro assays revealed that MEG2 plays a vital role in CRC cell proliferation, invasion, and apoptosis. In addition, mechanism analysis validated miR-21 as a direct regulator of MEG2, and miR-21 plays a critical role in promoting proliferation, invasion, and suppression of apoptosis in CRC by targeting MEG2. Taken together, this study demonstrates the significant role for miR-21 in regulating MEG2 in CRC and may represent a potential target for CRC therapy.