Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, yet the molecular changes that occur in the bloodstream as the disease advances remain poorly understood. In particular, how p53—a key tumor suppressor—interacts with circulating proteins at different stages of CRC has not been well characterized. In this discovery-phase study, we analyzed plasma samples from patients with CRC stages I–IV using high-resolution LC–MS/MS. Stage-specific proteins were identified and cross-validated with transcriptomic data, revealing TP53 as a central hub in multiple functional networks. Enrichment analyses highlighted progressive changes in pathways linked to immune surveillance, complement activation, and cellular stress responses. Early-stage disease showed signals consistent with tumor suppression and immune regulation, while advanced stages were enriched in proteins associated with metastasis and therapy resistance. Notably, KLHL40 (Stage I) and FKBP1A (Stage III) emerged as potential stage-specific circulating biomarkers with functional links to p53 signaling. These findings outline a plasma-based molecular map of p53-associated protein networks across CRC progression and point to candidate biomarkers that warrant validation in larger, independent, and longitudinal studies. © 2025 Elsevier B.V., All rights reserved.