Background: Colorectal cancer (CRC) is a leading cause of death worldwide. Despite its preventability through screening, compliance still needs to improve due to the invasiveness of current tools. There is a growing demand for validated molecular biomarker panels for minimally invasive blood-based CRC screening. This study assessed the diagnostic accuracy of four promising blood-based CRC biomarkers, individually and in combination. Methods: This case–control study involved plasma samples from 124 CRC cases and 124 age- and sex-matched controls. Biomarkers tested included methylated DNA encoding the Septin-9 gene (mSEPT9) using Epi proColon^® 2.0 CE, insulin-like growth factor binding protein 2 (IGFBP2), dickkopf-3 (DKK3), and pyruvate kinase M2 (PKM2) by ELISA. Diagnostic accuracy was measured using the receiver operating characteristic (ROC), area under the curve (AUC), as well as sensitivity and specificity. Results: Diagnostic accuracy for mSEPT9, IGFBP2, DKK3, and PKM2 was 62.9% (95% CI: 56.8–62.9%), 69.7% (95% CI: 63.1–69.7%), 61.6% (95% CI: 54.6–61.6%), and 50.8% (95% CI: 43.4–50.8%), respectively. The combined biomarkers yielded an AUC of 74.4% (95% CI: 68.1–80.6%), outperforming all biomarkers except IGFBP2. Conclusions: These biomarkers show potential for developing a minimally invasive CRC detection tool as an alternative to existing approaches, potentially increasing adherence, early detection, and survivorship.