Ultraconserved regions (UCRs) are 481 segments that have been strictly conserved among many mammalian species for hundreds of years. Their transcribed products belong to long non‑coding RNAs and are closely involved in the progression of various tumors. uc.338 has been reported to promote cell proliferation in hepatocellular and lung cancers. However, the role of uc.338 in colorectal cancer (CRC) proliferation remains unclear. In the present study, we first detected the expression of uc.338 in human tissues and analyzed the relationship between uc.338 expression and clinical features of CRC. We then investigated the biological function of uc.338 in CRC proliferation in vitro and in vivo. Finally, we explored the potential mechanism by which uc.338 promotes the proliferation of CRC cells. Our results indicated that uc.338 was upregulated in CRC tissues and higher uc.338 expression was associated with a larger tumor size, deeper invasion, increased lymph node metastasis and poorer prognosis. Further investigations in vivo and in vitro revealed that uc.338 could promote proliferation and cell cycle G1/S transition, and might target p21 downregulation and cyclin D1 upregulation via the PI3K/AKT pathway in CRC cells. Thus, our findings suggested that uc.338 acts as an oncogene by promoting proliferation in CRC cells, and could become a novel target for CRC detection and therapy.