BACKGROUND: With the rising diagnostic rate of gallbladder polypoid lesions (GPLs), differentiating benign cholesterol polyps from gallbladder adenomas with a higher preoperative malignancy risk is crucial. This study aimed to establish a preoperative prediction model capable of accurately distinguishing between gallbladder adenomas and cholesterol polyps using machine learning algorithms. MATERIALS AND METHODS: We retrospectively analysed the patients' clinical baseline data, serological indicators, and ultrasound imaging data. Using 12 machine learning algorithms, 110 combination predictive models were constructed. The models were evaluated using internal and external cohort validation, receiver operating characteristic curves, area under the curve (AUC) values, calibration curves, and clinical decision curves to determine the best predictive model. RESULTS: Among the 110 combination predictive models, the Support Vector Machine + Random Forest (SVM + RF) model demonstrated the highest AUC values of 0.972 and 0.922 in the training and internal validation sets, respectively, indicating an optimal predictive performance. The model-selected features included gallbladder wall thickness, polyp size, polyp echo, and pedicle. Evaluation through external cohort validation, calibration curves, and clinical decision curves further confirmed its excellent predictive ability for distinguishing gallbladder adenomas from cholesterol polyps. Additionally, this study identified age, adenosine deaminase level, and metabolic syndrome as potential predictive factors for gallbladder adenomas. CONCLUSION: This study employed the machine learning combination algorithms and preoperative ultrasound imaging data to construct an SVM + RF predictive model, enabling effective preoperative differentiation of gallbladder adenomas and cholesterol polyps. These findings will assist clinicians in accurately assessing the risk of GPLs and providing personalised treatment strategies.