Powerful and reliable colorectal cancer (CRC) prognostic biomarkers that can be related to the risk of the disease progression and severity is still a great challenge. This study aimed to evaluate serum calprotectin (CP) potential association with CRC development and poor outcomes. Results revealed that elevated serum CP was significantly (P<0.05) related to CRC (45.74 (27.4-58.8) ng/mL) development compared to healthy controls (6.1 (4.3-8.8) ng/mL) and patients with benign polyps (32.5 (29.2-38.8) ng/mL). Compared to CEA (AUC=0.713), it had a superior ability (AUC=0.808) to differentiate CRC cases. Serum CP elevated levels (ng/mL) was significantly associated with tumor aggressiveness features like late stages (47.5 (28.7-70.5) vs. 43.4 (24.8-51.9); P=0.0032), lymph node invasion (45.1 (22.6-87.1) vs. 46.2 (27.7-56.9); P=0.0344), distant metastasis (43.6 (19.6-109.9) vs. 46.2 (27.7-56.9); P=0.0423), high grades (54.6 (38.2-87.4) vs. 39.0 (22.0-48.9); P=0.0001), and large size (46.7 (31.3 51.6) vs. 26.7 (17.7-42.4); P=0.0113). CP was also significantly correlated with CEA (r =0.399; P =0.002) in CRC patients. In conclusion, serum CP protein appears to be a reliable CRC biomarker that could act in clinical practice as a non-specific marker for monitoring CRC progression and preventing poor outcomes.