Cancer indeed represents a significant public health challenge, and unplanned extubation of peripherally inserted central catheter (PICC-UE) is a critical concern in patient safety. Identifying independent risk factors and implementing high-quality assessment tools for early detection in high-risk populations can play a crucial role in reducing the incidence of PICC-UE among patients with cancer. Precise prevention and treatment strategies are essential to improve patient outcomes and safety in clinical settings. This study aims to identify the independent risk factors associated with PICC-UE in patients with cancer and to construct a predictive model tailored to this group, offering a theoretical framework for anticipating and preventing PICC-UE in these patients. Prospective data were gathered from January to December 2022, encompassing patients with cancer with PICC at Xiangya Hospital, Central South University. Each patient underwent continuous monitoring until the catheter's removal. The patients were categorized into 2 groups: the UE group (n=3107) and the non-UE group (n=284). Independent risk factors were identified through univariate analysis, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate analysis. Subsequently, the 3391 patients were classified into a train set and a test set in a 7:3 ratio. Utilizing the identified predictors, 3 predictive models were constructed using the logistic regression, support vector machine, and random forest algorithms. The ultimate model was selected based on the receiver operating characteristic (ROC) curve and TOPSIS (Technique for Order Preference by Similarity to Ideal Solution) synthesis analysis. To further validate the model, we gathered prospective data from 600 patients with cancer at the Affiliated Hospital of Qinghai University and Hainan Provincial People's Hospital from June to December 2022. We assessed the model's performance using the area under the curve of the ROC to evaluate differentiation, the calibration curve for calibration capability, and decision curve analysis (DCA) to gauge the model's clinical applicability. Independent risk factors for PICC-UE in patients with cancer were identified, including impaired physical mobility (odds ratio [OR] 2.775, 95% CI 1.951-3.946), diabetes (OR 1.754, 95% CI 1.134-2.712), surgical history (OR 1.734, 95% CI 1.313-2.290), elevated D-dimer concentration (OR 2.376, 95% CI 1.778-3.176), targeted therapy (OR 1.441, 95% CI 1.104-1.881), surgical treatment (OR 1.543, 95% CI 1.152-2.066), and more than 1 catheter puncture (OR 1.715, 95% CI 1.121-2.624). Protective factors were normal BMI (OR 0.449, 95% CI 0.342-0.590), polyurethane catheter material (OR 0.305, 95% CI 0.228-0.408), and valved catheter (OR 0.639, 95% CI 0.480-0.851). The TOPSIS synthesis analysis results showed that in the train set, the composite index (Ci) values were 0.00 for the logistic model, 0.82 for the support vector machine model, and 0.85 for the random forest model. In the test set, the Ci values were 0.00 for the logistic model, 1.00 for the support vector machine model, and 0.81 for the random forest model. The optimal model, constructed based on the support vector machine, was obtained and validated externally. The ROC curve, calibration curve, and DCA curve demonstrated that the model exhibited excellent accuracy, stability, generalizability, and clinical applicability. In summary, this study identified 10 independent risk factors for PICC-UE in patients with cancer. The predictive model developed using the support vector machine algorithm demonstrated excellent clinical applicability and was validated externally, providing valuable support for the early prediction of PICC-UE in patients with cancer.