Background <p>Colorectal cancer (CRC) is a leading malignancy with limited treatment options, often characterized by elevated ribosome biogenesis that supports rapid cell growth. This study investigates the role of the ribosomal protein RPS17 in CRC progression and its potential as a prognostic biomarker and therapeutic target.</p> Methods <p>Bioinformatics analysis of TCGA-COAD and GSE106584 datasets identified differentially expressed genes (DEGs) linked to ribosome biogenesis. Functional enrichment analyses (KEGG/GO) and LASSO regression were utilized to construct a seven-gene prognostic model, which included RPS17. Clinical validation assessed RPS17 expression in CRC tissues, while in vitro experiments evaluated its impact on CRC cell proliferation, migration, apoptosis, and ribosome biogenesis. Mechanistic studies explored RPS17’s regulation of the MDM2/p53 axis.</p> Results <p>Most ribosome biogenesis-related genes were upregulated in CRC, correlating with malignancy. The prognostic model demonstrated robust predictive accuracy in training, testing, and external cohorts. RPS17 was significantly overexpressed in CRC tissues and associated with aggressive clinical features. Functional assays revealed that RPS17 knockdown suppressed CRC cell proliferation, migration, and colony formation, while inducing apoptosis. Mechanistically, molecular docking predicted that RPS17 interacts with MDM2 and p53. Furthermore, RPS17 depletion reduced ribosomal RNA (rRNA) expression and RNA synthesis, thereby inhibiting ribosome biogenesis, and modulated MDM2/p53 signaling to impair tumor cell survival.</p> Conclusions <p>RPS17 promotes CRC progression by enhancing ribosome biogenesis and perturbing the MDM2/p53 pathway, highlighting its dual role as a prognostic biomarker and therapeutic target. These findings highlight the potential of RPS17 as a prognostic biomarker and therapeutic target for CRC.</p>