Objectives To differentiate Glioblastomas (GBM) and Brain Metastases (BM) using a radiomic features-based Machine Learning (ML) classifier trained from post-contrast three-dimensional T1-weighted (post-contrast 3DT1) MR imaging, and compare its performance in medical diagnosis versus human experts, on a testing cohort. Methods We enrolled 143 patients (71 GBM and 72 BM) in a retrospective bicentric study from January 2010 to May 2019 to train the classifier. Post-contrast 3DT1 MR images were performed on a 3-Tesla MR unit and 100 radiomic features were extracted. Selection and optimization of the Machine Learning (ML) classifier was performed using a nested cross-validation. Sensitivity, specificity, balanced accuracy, and area under the receiver operating characteristic curve (AUC) were calculated as performance metrics. The model final performance was cross-validated, then evaluated on a test set of 37 patients, and compared to human blind reading using a McNemar’s test. Results The ML classifier had a mean [95% confidence interval] sensitivity of 85% [77; 94], a specificity of 87% [78; 97], a balanced accuracy of 86% [80; 92], and an AUC of 92% [87; 97] with cross-validation. Sensitivity, specificity, balanced accuracy and AUC were equal to 75, 86, 80 and 85% on the test set. Sphericity 3D radiomic index highlighted the highest coefficient in the logistic regression model. There were no statistical significant differences observed between the performance of the classifier and the experts’ blinded examination. Conclusions The proposed diagnostic support system based on radiomic features extracted from post-contrast 3DT1 MR images helps in differentiating solitary BM from GBM with high diagnosis performance and generalizability.