Introduction: Colorectal cancer (CRC) is the most common type of gastrointestinal tract cancers. This investigation aim was to assess the expression of miR-576-3p and miR-613 in CRC patients in addition to NDRG2 and YKL40 serum levels determination to decide their diagnostic and prognostic significance. Methods: Sixty early diagnosed CRC patients prior to any treatment in addition to twelve healthy subjects were enrolled in this study. Blood samples were taken from subjects and allowed for clotting and centrifugation, then the collected sera were stored at -80ºC till it were used for detection of our molecular biomarkers. The mature miRNAs expressions ( miR-576-3p and miR-613 ) were detected in serum by qRT-PCR, while NDRG2 and YKL40 serum levels were determined by ELISA. In addition, the correlation of the measured parameters with the clinicopathological data of the patients was investigated. Results: The study results showed that both miRNA-576-3p and miRNA-613 were down-regulated in CRC patients with fold change 0.33, 0.36; respectively. A significant positive correlation was observed between miR-576-3p and miR-613 (r = 0.75, p < 0.001). NDRG2 serum levels were decreased in patients compared to the control group but the decrease wasn’t statistically significant. On the other hand, it was observed that YKL40 serum level was significantly increased in CRC patients compared to control (p-value < 0.001). Furthermore, YKL40 showed a very high diagnostic value (AUC = 0.97, specificity = 91.7%, sensitivity = 96%, p-value = 0.0001). Conclusion: The observations of this investigation concluded that, the expressions of miR-576-3p and miR-613 in addition to YKL40 serum levels determinations may help in the diagnosis of CRC.