Background: Despite advances in the development of efficient chemotherapy, the treatment of colorectal cancer (CRC) remains a challenge due to acquired chemoresistance. It has been reported that microRNAs (miRNAs) dysregulation is associated with the development of chemoresistance. Recently, the expression of miR-199b-3p has been found to be significantly different between cetuximab (CTx)-resistant and -sensitive CRC cells. However, its role and the underlying mechanisms in acquired chemoresistance to CTx in CRC are still obscure. Methods: Here we report that miR-199b-3p is significantly up-regulated in both CTx-resistant (CTxR) CRC tissues and cell lines. Results: Functional assays showed that suppressing miR-199b-3p could improve the sensitivity of CRC-CTxR cells to CTx, thereby reducing cell proliferation, migration and invasion, and enhancing cell apoptosis. Mechanistic studies revealed that CRIM1 is a direct target of miR-199b-3p in CRC-CTxR cells; and the effect of miR-199b-3p on CTx-resistance was exerted by regulating the Wnt/beta-catenin signaling pathway via CRIM1. Furthermore, mice xenograft models were established and confirmed that down-regulating miR-199b-3p restores the inhibition effect of CTx on tumor growth in CRC-CTxR. Collectively, our data suggest that silencing miR-199b-3p could enhance the anti-tumor effects of CTx on CTx-resistant CRC in vitro and in vivo by activating Wnt/P-catenin signaling via the down-regulation of CRIM1. Conclusions: Our findings suggest miR-199b-3p might serve as a promising therapeutic target against CTx resistant CRC, and provide scientific information for exploring novel strategies of improving the efficacy of CTx for CRC patients.