Although rRNA metabolism-related genes have been reported to be associated with human cancer, a systematic assessment of rRNA metabolism-related genes across human cancers is lacking. Thus, we performed a Pan-cancer analysis of rRNA metabolism-related genes across 20 human cancers. Here, we examined mRNA expression, mutation, DNA methylation, copy number variation (CNV) and clinical landscape of rRNA metabolism-related genes in more than 8600 patients across 20 human cancers from The Cancer Genome Atlas (TCGA) dataset. Besides, ten independent Gene Expression Omnibus (GEO) datasets, Cancer Cell Line Encyclopedia (CCLE) dataset and Project Achilles dataset were used to verify our study. A landscape of rRNA metabolism-related genes was established across 20 human cancers. The results suggest that rRNA metabolism-related genes are upregulated in multiple cancers, particularly in digestive and respiratory system cancers. Most of the upregulated genes were driven by CNV gain rather than mutation or DNA hypomethylation. We systematically identified CNV-driven rRNA metabolism-related genes with clinical relevance, including EXOSC8. Finally, functional experiments confirmed the oncogenic roles of EXOSC8 in colorectal carcinoma. Our study highlights the important roles of rRNA metabolism-related genes in tumorigenesis as prognostic biomarkers.