Aberrant N⁶-methyladenosine (m⁶A) modification on mRNA is correlated with cancer progression. However, the role of m⁶A on ribosomal RNA (rRNA) in cancer remains poorly understood. Our current study reveals that METTL5/TRMT112 and their mediated m⁶A modification at the 18S rRNA 1832 site (m⁶A₁₈₃₂) are elevated in nasopharyngeal carcinoma (NPC) and promote oncogenic transformation in?vitro and in?vivo. Moreover, loss of catalytic activity of METTL5 abolishes its oncogenic functions. Mechanistically, m⁶A₁₈₃₂ 18S rRNA modification facilitates the assembly of 80S ribosome via bridging the RPL24-18S rRNA interaction, therefore promoting the translation of mRNAs with 5′ terminal oligopyrimidine (5′ TOP) motifs. Further mechanistic analysis reveals that METTL5 enhances HSF4b translation to activate the transcription of HSP90B1, which binds with oncogenic mutant p53 (mutp53) protein and prevents it from undergoing ubiquitination-dependent degradation, therefore facilitating NPC tumorigenesis and chemoresistance. Overall, our findings uncover an innovative mechanism underlying rRNA epigenetic modification in regulating mRNA translation and the mutp53 pathway in cancer.