Background: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an RNA-binding protein, is associated with tumorigenesis and progression. However, the exact molecular mechanisms of IGF2BP3 in colorectal cancer (CRC) oncogenesis, progression, and drug resistance remain largely unclear.Methods: Transcriptome-sequencing, bioinformatics analysis, Western blot, and immunohistochemistry were performed to evaluate the expression of IGF2BP3 in CRC. Gene enrichment analysis and qPCR were used to assess the downstream targets of IGF2BP3. The molecular mechanisms of IGF2BP3 on CRC progression were explored through RNA stability assay, m6A dot-blot, luciferase reporter assay, and MeRIP assay. In vitro and in vivo experiments were conducted to investigate the effects of IGF2BP3 on oncogenesis, progression and sensitivity to cetuximab of CRC. Results: IGF2BP3 was upregulated in CRC tissues. Clinically, elevated IGF2BP3 level was predictive of a poor prognosis. Functionally, IGF2BP3 enhanced CRC tumorigenesis and progression in vitro and in vivo. Mechanistically, IGF2BP3 promoted epidermal growth factor receptor (EGFR) mRNA stability and translation, then further activated the EGFR pathway by serving as a reader in an N6-methyladenosine (m6A)-dependent manner by cooperating with METTL14. Furthermore, IGF2BP3 increases drug resistance of CRC cells to the EGFR-targeted antibody cetuximab. Conclusions: IGF2BP3 upregulation serve as an important oncogene in the development of CRC. It stabilizes EGFR mRNA via an m6A-dependent manner and further promotes CRC progression and drug resistance to cetuximab. Targeting IGF2BP3 and m6A modification offers rational therapeutic targets in CRC patients.