Searching for clinical sensible biomarkers that can be served as an alternative tool for colorectal cancer (CRC) early diagnosis and prognosis is still a great challenge. This study aimed to evaluate serum amyloid A (SAA) potential role in CRC diagnosis and prediction of poor disease progression. Results revealed that elevated SAA was significantly (P<0.0001) associated with CRC (33.15 (30.1-35.5) ng/mL) compared to patients with benign polyps (14.2 (10.8-19.7) ng/mL) and healthy (5.0 (3.2-7.0) ng/mL) controls. It had a great ability (AUC=0.995) to differentiate CRC patients from all non-cancer individuals. SAA levels was significantly (P<0.05) impacted on CRC invasiveness as its elevated levels were associated with including tumor late stages, lymph node invasion, distant metastasis, high grades and large tumor size. Moreover, SAA was significantly correlated with CEA (r=0.644; P=0.0001) in CRC patients. In conclusion, SAA protein appears to be a reliable marker for CRC, which could be recommended for initial differentiation of CRC from benign polyps. It also could act in clinical routine as a non-specific tumor marker for monitoring CRC progression to prevent poor outcomes.