Background <p>Metachronous liver metastasis (MLM) after primary resection of colorectal cancer (CRC) substantially worsens patient prognosis. Vascular endothelial growth factor (VEGF) is a highly bioactive proangiogenic protein. However, few studies have used serum VEGF to predict CRC liver metastasis, particularly MLM. This study investigated the predictive value of preoperative serum VEGF levels for the development of MLM in patients with CRC and developed a novel nomogram.</p> Methods <p>Data from 229 patients with CRC who underwent radical resection of the primary tumor at the First Affiliated Hospital of Henan University between June 2019 and June 2022 were retrospectively analyzed. Patients were divided into training (<i>n</i> = 153) and validation (<i>n</i> = 76) cohorts. Independent risk factors for MLM were identified in the training cohort and were used to develop and validate the nomogram.</p> Results <p>Preoperative VEGF levels &gt; 436.81 pg/mL, preoperative carcinoembryonic antigen levels &gt; 5.0 ng/mL, T stage, N stage, and mismatch repair proficiency were independent risk factors for MLM and were used to develop the nomogram. The concordance index of the training cohort was 0.849 (95% confidence interval: 0.765–0.933). Calibration curve analysis revealed that the standard curve fit well with the predicted curve. Receiver operating characteristic curve analysis demonstrated the nomogram’s high efficiency. Decision curve analysis confirmed the nomogram’s significant clinical value.</p> Conclusion <p>We developed a novel nomogram including VEGF and mismatch repair proficiency in this study which were rarely reported in previous studies and the novel nomogram exhibits good discriminative ability and high accuracy in predicting MLM in patients with CRC. The identification of patients at a high risk of MLM would enable closer monitoring and timely interventions.</p>