Abstract Introduction/Objective Colorectal cancer (CRC) is the third-most common cancer worldwide, and early detection is vital for successful treatment and improved outcomes. Current screening methods such as colonoscopy, fecal occult blood tests, and stool DNA tests have limitations such as patient discomfort, cost, and low sensitivity and specificity most commonly diagnosed cancer worldwide with a high mortality rate. Early detection remains a crucial factor in reducing the burden of CRC. Currently, the gold standard for CRC diagnosis is colonoscopy, but it may not be feasible for widespread screening due to its invasiveness, cost, and patient compliance issues. Therefore, there is a great need to identify reliable biomarkers that can detect CRC at an early stage. This study aimed to evaluate the effectiveness of updated novel biomarkers for early detection of CRC. Methods/Case Report This study was conducted on 158 patients with suspected or confirmed CRC. The study population included patients of both genders, aged above 18 years, and with a history of CRC or other relevant risk factors. Blood samples were collected from all included patients, and the biomarkers (CTCS, miRNAs, ctDNA, and Methylated DNA markers ) were measured using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) tests. Novel biomarkers compared their diagnostic performance with existing biomarkers such as fecal occult blood tests (FOBTs), fecal immunochemical tests (FITs), and CEA. Results (if a Case Study enter NA) The studied biomarkers (CTCs, microRNAs, ctDNA, and Methylated DNA markers) have high sensitivity from 78.8 % to 96.72% and accuracy from 83.76% to 94.83% as well as their cut-off which approved the objective of this study. Overall, these novel biomarkers show promise for early detection of colorectal cancer and may improve screening and early detection efforts. Conclusion The evaluation of the studied biomarkers (Circulating Tumor Cells, microRNAs, Circulating tumor DNA, and Methylated DNA markers) for early detection of CRC has substantial clinical and public health implications. The identification of reliable biomarkers for CRC screening can avoid unnecessary colonoscopies, reduce the burden on healthcare costs, and improve the detection of early-stage CRC.