Background: A fair amount of microcalcifications sent for biopsy are false positives. The study investigates whether quantitative radiomic features extracted from digital breast tomosynthesis (DBT) can be an additional and useful tool to discriminate between benign and malignant BI-RADS category 4 microcalcification. Methods: This retrospective study included 252 female patients with BI-RADS category 4 microcalcifications. The patients were divided into two groups according to micro-histopathology: 126 patients with benign lesions and 126 patients with certain or possible malignancies. A total of 91 radiomic features were extracted for each patient, and the 12 most representative features were selected by using the agglomerative hierarchical clustering method. The binary classification task of the two groups was carried out by using four different machine-learning algorithms (i.e., linear support vector machine (SVM), radial basis function (RBF) SVM, logistic regression (LR), and random forest (RF)). Accuracy, sensitivity, sensibility, and the area under the curve (AUC) were calculated for each of them. Results: The best performance was achieved using the RF classifier (AUC = 0.59, 95% confidence interval 0.57–0.60; sensitivity = 0.56, 95% CI 0.54–0.58; specificity = 0.61, 95% CI 0.59–0.63; accuracy = 0.58, 95% CI 0.57–0.59). Conclusions: DBT-based radiomic analysis seems to have only limited potential in discriminating benign from malignant microcalcifications.