The aim of this study was to assess the diagnostic ability of radiomics combined with multiple machine learning algorithms to differentiate pancreatic ductal adenocarcinoma (PDAC) from pancreatic neuroendocrine tumor (pNET). This retrospective study included a total of 238 patients diagnosed with PDAC or pNET. Using specialized software, radiologists manually mapped regions of interest (ROIs) from computed tomography images and automatically extracted radiomics features. A total of 45 discriminative models were built by five selection algorithms and nine classification algorithms. The performances of the discriminative models were assessed by sensitivity, specificity and the area under receiver operating characteristic curve (AUC) in the training and validation datasets. Using the combination of Gradient Boosting Decision Tree (GBDT) as the selection algorithm and Random Forest (RF) as the classification algorithm, the optimal diagnostic ability with the highest AUC was presented in the training and validation datasets. The sensitivity, specificity and AUC of the model were 0.804, 0.973 and 0.971 in the training dataset and 0.742, 0.934 and 0.930 in the validation dataset, respectively. The combination of radiomics and multiple machine learning algorithms showed the potential ability to discriminate PDAC from pNET. We suggest that multi-algorithm modeling should be considered for similar studies in the future rather than using a single algorithm empirically.