Colorectal cancer (CRC) is the seventh most common cancer in Egypt, and more than half of the patients are under the age of 50. Here, we aimed to assess the levels of circulating Dermokine (DMKN) and cytoplasmic anti-apoptotic protein, Bcl-2 for detecting CRC in the earlier stages possible. The levels of DMKN, Bcl-2, Carcinoembryonic antigen (CEA), and Carbohydrate antigen 19.9 were determined using ELISA in the sera of 53 CRC patients, 18 ulcerative colitis patients, and 24 healthy individuals. Statistical analyses were performed using the SPSS program. Serum levels of DMKN and Bcl-2 were significantly higher (p < 0.0001) in CRC patients than in non-cancer individuals. Highly significant correlations were recorded between levels of DMKN and Bcl-2 and the pathological TNM tumor characteristics. At the best cut-off level (68-pg/mL), the DMKN assay showed high degrees of sensitivity (87%), specificity (100%), and accuracy (91%) in comparison with investigated biomarkers. Furthermore, regression analysis revealed a DKB-Score based on DMKN and Bcl-2 with an AUROC of 0.991. The developed score showed a high degree of efficiency (97.4%) for discriminating CRC patients from controls. In conclusion, the assessment of serum DMKN either alone or simultaneously with Bcl-2 has a potential role in discriminating CRC from premalignant patients.