Owing to the subtle symptoms and low sensitivity of colorectal cancer (CRC), such as rectal bleeding, anemia, and abdominal pain, CRC generally occurs in late stages. This leads to delayed diagnosis and reduced treatment efficiency. Therefore, novel and effective CRC markers are needed. In this study, we conducted circRNA expression profiling on GSE datasets and identified circ-CCDC66 as a potential marker. Through qPCR analysis of plasma samples from 50 CRC patients, 50 with colorectal polyps, and 50 healthy individuals, circ-CCDC66 emerged as a promising biomarker for CRC detection capable of identifying polyps among healthy individuals. Furthermore, plasma circ-CCDC66 levels exhibited superior diagnostic accuracy, with an AUC of 0.920, compared to traditional markers, such as serum CEA and CA19-9. Remarkably, the combined detection of circ-CCDC66, CEA, and CA19-9 further increased the AUC for distinguishing the colorectal polyps' group from the healthy control group to 0.991, with sensitivity and specificity increasing to 98% and 96%, respectively. Additionally, a circ-CCDC66-miRNA-mRNA regulatory network was established to provide insight into how circ-CCDC66 influences CRC pathways. This pioneering study highlights circ-CCDC66's clinical relevance as a blood-based diagnostic marker for CRC and offers valuable insights into future developments in the diagnosis and treatment of the disease.