Colorectal cancer (CRC) is one of the most common cancers worldwide. In this study, we explored the role of RNA binding motif protein 15 (RBM15)-mediated MyD88 mRNA N6-methyladenosine (m6A) in CRC development. Cell proliferation, apoptosis, and invasion were detected by EdU, Annexin V-FITC/PI staining, and Transwell assays, respectively. RBM15 and MyD88 expression was detected by RT-qPCR and Western blot. RNA-seq, RIP-seq, and MeRIP-seq were used for RBM15 downstream target gene prediction and expression detection. In this research, we confirmed that RBM15 was highly expressed in CRC tissues and was negatively correlated with overall and disease-free survival rate. Silencing RBM15 significantly inhibited the proliferative and invasive abilities and promoted cell apoptosis in the CRC cell lines (SW480 and HCT116). Moreover, tumor growth and CRC liver metastasis were inhibited by silencing RBM15 . m6A methylation level was decreased in RBM15-silenced SW480 and HCT116 cells. MyD88 was the target mRNA of RBM15-mediated m6A methylation in CRC. MyD88 was lowly expressed in CRC and negatively correlated with RBM15 expression. Taken together, RBM15 silencing inhibited the CRC growth and metastasis and . RBM15 mediated m6A methylation modification of MyD88 mRNA in CRC cells.