Colorectal cancer (CRC) is the second major cause of tumor-related deaths. MicroRNAs (miRNAs) have pivotal roles in CRC progression. Here, we describe the effect of miR-181d on CRC cell metabolism and underlying molecular mechanism. Our data firmly demonstrated that knockdown of miR-181d suppressed CRC cell proliferation, migration, and invasion by impairing glycolysis. Mechanistically, miR-181d stabilized c-myc through directly targeting the 3'-UTRs of CRY2 and FBXL3, which subsequently increased the glucose consumption and the lactate production. Inhibition of c-myc via siRNA or small molecular inhibitor abolished the oncogenic effects of miR-181d on the growth and metastasis of CRC cells. Furthermore, c-myc/HDAC3 transcriptional suppressor complex was found to co-localize on the CRY2 and FBXL3 promoters, epigenetically inhibit their transcription, and finally induce their downregulation in CRC cells. In addition, miR-181d expression could be directly induced by an activation of c-myc signaling. Together, our data indicate an oncogenic role of miR-181d in CRC by promoting glycolysis, and miR-181d/CRY2/FBXL3/c-myc feedback loop might be a therapeutic target for patients with CRC.