Oxaliplatin, as a first-line drug, frequently causes chemo-resistance in colorectal cancer (CRC). The role of N6-methyladenosine (m6A) modification in multiple biological functions has been well studied. However, the molecular mechanisms underlying m6A methylation in modulating anti-cancer drug resistance in CRC remain obscure. In the present study, we found that YTH m6A RNA-binding protein 3 (YTHDF3) was highly expressed in oxaliplatin-resistant (OXAR) CRC tissues and cells. Moreover, we observed that YTHDF3 could recognize the 5' untranslated region of significantly m6A-methylated RNAs, which were associated with tumor resistance and recruit eukaryotic translation initiation factor 3 subunit A (eIF3A) to facilitate the translation of these target genes. Furthermore, we determined that eukaryotic translation initiation factor 2 alpha kinase 2 (eIF2AK2) bridged YTHDF3 and eIF3A, enhancing the stability of the YTHDF3/eIF3A complex in OXAR CRC cells. Taken together, our data identified YTHDF3 as a novel hallmark and revealed the molecular mechanism of YTHDF3 on gene translation via coordination with eIF2AK2 in OXAR CRC cells.