Brain metastasis is a major cause of cancer mortality, but its molecular mechanisms are severely understudied. In addition, little is known regarding the role of m6A reader YTHDF3 in human diseases. Here, we show that YTHDF3 overexpression clinically correlates with brain metastases in breast cancer patients. YTHDF3 promotes cancer cell interactions with brain endothelial cells and astrocytes, blood-brain barrier extravasation, angiogenesis, and outgrow. Mechanistically, YTHDF3 enhances the translation of m6A-enriched transcripts for ST6GALNAC5, GJA1, and EGFR, all associated with brain metastasis. Furthermore, overexpression of YTHDF3 in brain metastases is attributed to increased gene copy number and the autoregulation of YTHDF3 cap-independent translation by binding to m6A residues within its own 5′ UTR. Our work uncovers an essential role of YTHDF3 in controlling the interaction between cancer cells and brain microenvironment, thereby inducing brain metastatic competence. Display omitted •YTHDF3 overexpression clinically correlates with breast cancer brain metastases•Breast cancer brain metastases have YTHDF3 gene copy gain and autoregulation•YTHDF3 plays critical roles in multiple steps of brain metastasis cascade•YTHDF3 promotes translation of the key brain metastatic genes ST6GALNAC5 and GJA1 Chang et al. report that YTHDF3 overexpression associates with breast cancer brain metastasis and confers poor survival. Mechanistically, YTHDF3 enhances the expression of m6A-enriched transcripts that promote cancer cell-brain microenvironment interactions and brain metastasis.