Colorectal cancer (CRC) is prevalent worldwide and novel diagnostic and prognostic biomarkers are needed to improve precision medicine. Circular RNAs (circRNAs) are currently being considered as emerging tumor biomarkers. Herein, we aimed to explore the possible clinical application of circRNAs in the early diagnosis and prognostic prediction of CRC. First, candidate circRNA was selected by integrating analysis of Gene Expression Omnibus (GEO) database using GEO2R program. ROC curve analysis demonstrated the predictive values and likelihood ratios of circ_001659 were satisfactory for the diagnosis of CRC, including patients in early-stage disease or patients with carcinoembryonic antigen (CEA)-negative status. Moreover, serum circ_001659 may be a novel biomarker in the assessment of successful treatment and remission of cancer tracking. We further investigated the oncogenic role of circ_001659. In vivo and in vitro experiments indicated that circ_001659 could promote CRC cell invasion and migration. Mechanistically, circ_001659 was localized in the nucleus, recruited the RBBP5 to Vimentin promoter and increased H3K4 trimethylation level on the Vimentin promoter region, which epigenetically activated Vimentin transcription. Our findings demonstrate that circ_001659 could be a useful serum biomarker for CRC diagnosis and prognosis. Targeting circ_001659 and its pathway may be meaningful for treating patients with CRC. Copyright © 2021 Elsevier Inc. All rights reserved.