Overcoming resistance to chemotherapy is an arduous challenge in the treatment of colorectal cancer (CRC), particularly since the underlying molecular mechanisms remain obscure. In the present study, we reported that miR‑874-3p was markedly downregulated in CRC tissues compared with that in adjacent normal colorectal epithelial tissues. Upregulation of miR-874-3p attenuated the chemoresistance of CRC cells to 5-fluorouracil (5-FU) in vitro and in vivo. Conversely, inhibition of miR-874-3p yielded an opposite effect. Furthermore, our results demonstrated that miR-874-3p directly inhibited the expression of transcriptional co-activators YAP and TAZ of the Hippo signaling pathway, resulting in the inactivation of the TEAD transcription. Thus, our findings clarify a novel mechanism by which miR-874-3p restores chemotherapeutic sensitivity of CRC to 5-FU, indicating that offering miR-874-3p mimics in combination with 5-FU may serve as a new therapeutic strategy to circumvent the chemoresistance in CRC.