Background Colorectal cancer is a common and lethal disease. It is estimated that approximately 145,600 new cases of large bowel cancer are diagnosed annually in the USA. MiRNA-223 and miRNA-182 have been reported in various cancers, such as lung, gastric, breast and colorectal cancer and proposed to be valid and reliable for diagnosis as well as prognosis. Aim This study aimed to determine the role of miR-223 and miR-182 as novel biomarkers for early detection and prognosis of CRC. Patient and Methods This case–control study was conducted at the department of Internal Medicine, Aswan University Hospital, in the period from the 1st of February 2020 to the 20th of April 2021. Thirty-five cases and thirty age- and sex-matched controls were included in the study. All patients were subject to complete clinical evaluation, routine investigations, occult blood in stool, serum levels of CEA and CA 19–9, serum levels of miR-223 and miR-182 by quantitative PCR. Results Significant difference between the two studied groups regarding biomarker changes was found. ROC curve analysis showed that the new markers had excellent diagnostic as well as prognostic criteria. Micro-RNA-223 diagnostic accuracy, sensitivity, specificity, PPV, NPV, FDR and FOR were 97%, 97.1%, 96.7%, 97%, 97%, 3.3% and 2.9%, respectively. Also, micro-RNA-182 diagnostic accuracy, sensitivity, specificity, PPV, NPV, FDR and FOR were 97%, 98%, 96%, 96%, 98%, 3.9% and 2%, respectively. Conclusion MiR-223 and miR-182 have been discovered to be relevant and reliable biomarkers for the early identification and prognosis of CRC. Increased levels of miR-223 and miR-182 were associated with increased risk of disease progression, and the more accurate the value of miR-223 and miR-182, the earlier the diagnosis of colorectal cancer.