Long noncoding RNAs (lncRNAs) participate in many biological processes by affecting gene expression at the posttranscriptional level. lncRNAs are dysregulated in colorectal cancer (CRC) and this dysregulation is closely related to tumorigenesis, metastasis, and prognosis. Although many lncRNAs have been identified in CRC, the relation between ZNF667 antisense RNA 1 (head to head; ZNF667-AS1, accession: NR_036521.1) and CRC remains unclear. In this study, a total of 2,218 differentially expressed genes and 428 differentially expressed lncRNAs were identified between tumor and pericarcinous tissues. They were mainly enriched in cancer pathways, chemokine signaling, phosphoinositide 3-kinase-protein kinase B signaling pathway, and others. Key lncRNAs, including ZNF667-AS1, and their corresponding genes, such as ankyrin 2 (ANK2), were downregulated in CRC tumor tissues. In addition, downregulated ZNF667-AS1 (NR_036521.1) expression is associated with poor prognosis and disease progression. Overexpression of ZNF667-AS1 (NR_036521.1) inhibited the proliferation, migration, and invasion of VOLO cells both in vitro and in vivo. Moreover, Janus kinase 2 (JAK2) and ANK2 were significantly down- and upregulated in the overexpressed ZNF667-AS1 VOLO cells compared to those in the negative-control group. Knockdown of ANK2 or overexpression of JAK2 significantly counteracted the inhibitory effects of overexpression of ZNF667-AS1 on LOVO cell proliferation and migration. Taken together, it is indicated in our research that ZNF667-AS1 interaction with ANK2/JAK2 maybe important in CRC progression. Overexpression of ZNF667-AS1 could inhibit the proliferation, migration, and invasion of CRC cells, which may be related with the high ANK2 and low JAK2 levels.