Aberrant levels of circulating microRNAs are potential biomarkers for the early detection of colorectal cancer. The aim of this study was to study miR-139-3p and miR-622 in serum as a non-invasive biomarker for colorectal cancer diagnosis. We applied quantitative polymerase chain reaction to determine the levels of miR-139-3p and miR-622 in 42 pairs of tumor and adjacent non-tumor tissues, and in serum samples of 117 patients and 90 control subjects. Our results showed that miR-139-3p was silenced whereas miR-622 was overexpressed in colorectal cancer. Similarly, serum miR-139-3p level was significantly lower in colorectal cancer patients than in control subjects whereas miR-622 was more frequently detectable in patients. ROC analysis showed that AUC of miR-139-3p was 0.9935, with a sensitivity of 96.6% and specificity of 97.8%. Serum miR-139-3p level showed high sensitivity and specificity for both early and late stage CRCs and proximal and distal CRCs. Detectable serum miR-622 showed a sensitivity of 87.5% and specificity of 63.5% for discriminating CRC patients, but the sensitivity dropped for late stage patients (72.7%). We also included analyses of the blood CEA level for comparing the diagnostic performance of these blood-based biomarkers. The median level in CRC patients (3.6 ng/ml) was significantly higher than that in control (1.8 ng/ml). The AUC value of CEA in diagnosing CRC patients was 0.7515. CEA showed a positive correlation with tumor stage and age of patients and its level was higher in male. Collectively, serum miR-139-3p has strong potential as a promising non-invasive biomarker in colorectal cancer detection.