Purpose Post-translational methionine oxidation (MetO) modulates peptide stability and signaling in colorectal cancer (CRC), influencing tumor progression and therapy response. This study aimed to develop a proteomics-and computational-guided framework to identify oxidation-filtered, stage-specific plasma peptide fragments (SPFs) with physicochemical stability, proteolytic resistance, and cell-penetrating potential, and to evaluate their suitability as peptide-drug conjugate (PDC) candidate in CRC. Methods Stage-specific plasma proteomics (ESI-nanoLC-MS/MS) identified 8,912 peptides across early (ESCRC) and advanced (ASCRC) CRC. MetO-based filtering and Venn selection yielded candidate SPFs evaluated using ProtParam (stability), PeptideCutter (protease susceptibility), and CellPPD (cell-penetrating motifs). Molecular docking (SeamDock) was performed with CRC chemotherapeutics, and PepATTRACT was used to assess peptide-protein interactions with target enzymes. Results Twenty-nine SPFs showed stage specificity and MetO enrichment; six were stable by ProtParam. An ORM2-derived peptide (SDVMYTDWK) displayed high stability (instability index 19.83; aliphatic index 73.12) and strong binding affinity with irinotecan (-6.8 kcal/mol). CellPPD predicted moderate CPP potential with amphipathicity (similar to 1.1), mild cationicity (+ 1), and near-neutral hydrophobicity (-0.37 to-0.42). PepATTRACT modeling revealed ORM2 interaction with DNA topoisomerase I (Top1) near the catalytic pocket, supporting its role as a targeted PDC candidate for irinotecan delivery. Conclusion This integrative proteomic-computational workflow identifies ORM2 as a naturally stable, moderately cell-penetrating peptide capable of selective drug delivery. The findings highlight a cost-effective strategy for rational PDC design and demonstrate ORM2's translational potential for targeted chemotherapy in early-onset and drug-resistant CRC.