microRNAs (miR) can potentially be used for categorizing the various subtypes of colorectal cancer (CRC) and predicting a patient's response to treatment with traditional anti-CRC therapies. We investigated how miR-1297 and its potential target molecule cyclin D2 (CCND2) might affect the progression of CRC. Thirty-two pairs of CRC specimens and corresponding samples of para-tumor tissue were collected and examined for their levels of miR-1297 and CCND2 expression. We also examined miR-1297 and CCND2 expression in cultured SW480 cells. The effects of modulated levels of miR-1297 and CCND2 on cell viability, anchorage-independent growth ability, proliferation, apoptosis, cell cycle distribution, migration, and invasion were detected using specific techniques. The possible regulatory effect of miR-1297 on CCND2 was investigated using dual luciferase assays. Our results showed that miR-1297 expression was downregulated in clinical CRC specimens, and such downregulation was associated with upregulated levels of CCND2 expression. Upregulation of miR-1297 and downregulation of CCND2 reduced the proliferation and metastasis potential of SW480 cells, but did not affect the apoptotic process. In addition, miR-1297 regulated CCND2 function by directly binding to the promoter sequence of the CCND2 gene, which would block CCND2-related signaling at the transcription level. Our findings validate the anti-CRC function of miR-1297 and pro-CRC function of CCND2. Our findings may assist in developing miR-based therapies against CRC.