Colorectal cancer (CRC) remains one of the most common cancers worldwide. Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes, including cell growth, differentiation, apoptosis, and cancer progression. However, the function of lncRNAs in the progression of CRC remains largely unknown. Here, we reported that HOXA cluster antisense RNA2 (HOXA-AS2) was upregulated in CRC. Increased HOXA-AS2 expression in CRC was associated with larger tumor size and higher clinical stage. In vitro experiments revealed that HOXA-AS2 knockdown significantly inhibited CRC cell proliferation by causing G1 arrest and promoting apoptosis, whereas HOXA-AS2 overexpression promoted cell proliferation. Further functional assays indicated that HOXA-AS2 overexpression significantly promoted cell migration and invasion by regulating the epithelial-mesenchymal transition (EMT). In conclusion, our study identifies HOXA-AS2C as a potential biomarker in CRC.