Colorectal cancer (CRC) ranks among the most aggressive malignancies globally, with advanced-stage patients exhibiting notably low survival rates. Consequently, there is an urgent imperative to identify novel biomarkers characterized by high sensitivity and specificity. Ribosomal RNA-derived small RNAs (rsRNAs), which originate from ribosomal RNAs, represent the most prevalent small noncoding RNAs (sncRNAs) in CRC tissues and plasma. Thus, the development of a diagnostic panel comprising multiple rsRNAs holds considerable significance for CRC diagnosis. Utilizing PANDORA-seq, we have, for the first time, delineated a novel sncRNA expression profile in CRC tissues and plasma, identifying rsRNAs as the predominant sncRNAs within these contexts. We identified six rsRNAs that were significantly upregulated in CRC plasma and subsequently constructed a co-diagnostic panel. This panel demonstrated an area under the curve (AUC) value of 0.898, which increased to 0.942 when combined with clinically utilized tumor markers, indicating robust diagnostic efficacy. Our study is the first to establish that rsRNAs are the most abundantly expressed sncRNAs in CRC tissues and plasma. We have developed an rsRNA panel with substantial diagnostic efficacy in CRC plasma, presenting promising potential as diagnostic biomarkers.