The complement system, a core component of innate immunity, plays a key role in the tumorigenesis and progression of colon cancer. Although dysregulation in proteins associated with the complement and coagulation cascades (CCC) pathway has been identified in colon cancer, comprehensive investigations in this area are still scarce. In the present study, differential expression analysis was performed on colon adenocarcinoma (COAD) obtained from the GEPIA2 database (www.gepia2.cancer-pku.cn), to compare gene expression profiles between tumor tissues and paired adjacent normal tissues. A threshold of |log2 fold change|>1 and a q-value cutoff of 0.01 were applied. A total of 88 genes from the CCC signaling pathway were cross-referenced with the differentially expressed genes (DEGs) identified in the GEPIA2 analysis. These extracted DEGs were further investigated through hub gene analysis, survival analysis and druggability assessment. The expression of one selected DEG, serpin family A member 1 (SERPINA1), was subsequently validated using colon tissue microarrays. Among the 88 proteins in the CCC pathway, differential expression analysis identified 19 downregulated [SERPING1, factor VIII (F8) and complement C3 (C3)] and 13 upregulated [including SERPINA1 and coagulation factor XII] candidates in COAD. Survival analysis demonstrated that four of these genes (C3, F8, SERPINA1 and SERPING1), were notably associated with patient survival rates. Immunohistochemical validation confirmed the upregulation of SERPINA1, and this elevated expression was associated with shorter survival in patients with colon cancer. The present study demonstrates widespread dysregulation of proteins in the CCC pathway in colon cancer. SERPINA1 emerges as a promising diagnostic biomarker and potential therapeutic target. Investigating SERPINA1 therefore offers valuable insights into colon cancer pathogenesis and guides the pursuit of novel therapeutic approaches.