To develop a nomogram model for distinguishing benign from malignant ampullary lesions more intuitive and accurate. A total of 124 patients with periampullary lesions from January 2016 to June 2020 were enrolled in this retrospective study. Their clinical information, ultrasound (US), dual contrast-enhanced ultrasound (DCEUS) and MRI image features were used for research. Twenty features were collected in our study. Random forest was used to select the first five most important indicators to construct the prediction model. Patients' age, common bile duct (CBD) diameter, the shape, vascularity, and boundary of lesion, lesion size with or without enlarged after CEUS, the enhancement patterns of arterial phase, the washout patterns of venous phase, CEUS diagnosis, and MRI diagnosis were statistically significant (p < 0.05). After screening for statistically significant indicators by random forest, the first five most important indicators were age, CBD diameter, the enhancement patterns of arterial phase, the washout patterns of venous phase, lesion size with or without enlarged after CEUS, which were used to construct nomogram. The area under curves (AUC) and 95% confidence intervals (CI) for nomogram, MRI + MRCP + DCEUS, DCEUS, MRI + MRCP were 0.98(0.94-1.00), 0.91(0.84-0.97), 0.89(0.80-0.98), 0.68(0.60-0.77), respectively. The sensitivity and specificity were 100.00% and 84.62% for nomogram, 88.29% and 92.31% for MRI + MRCP+DCEUS, 86.49% and 92.31% for DCEUS, 51.35%, and 100.00% for MRI + MRCP. We combined clinical indicators, gray-scale ultrasound characteristics, and CEUS characteristics to build the nomogram, which can be intuitively and accurately used for preoperative malignant prediction of ampullary lesion patients, worthy of clinical generalizability and application.