Background/Aim: Nowadays, Machine Learning (ML) algorithms have demonstrated remarkable progress in image-recognition tasks and could be useful for the new concept of precision medicine in order to help physicians in the choice of therapeutic strategies for brain tumours. Previous data suggest that, in the central nervous system (CNS) tumours, amino acid PET may more accurately demarcate the active disease than paramagnetic enhanced MRI, which is currently the standard method of evaluation in brain tumours and helps in the assessment of disease grading, as a fundamental basis for proper clinical patient management. The aim of this study is to evaluate the feasibility of ML on 11[C]-MET PET/CT scan images and to propose a radiomics workflow using a machine-learning method to create a predictive model capable of discriminating between low-grade and high-grade CNS tumours. Materials and Methods: In this retrospective study, fifty-six patients affected by a primary brain tumour who underwent 11[C]-MET PET/CT were selected from January 2016 to December 2019. Pathological examination was available in all patients to confirm the diagnosis and grading of disease. PET/CT acquisition was performed after 10 min from the administration of 11C-Methionine (401–610 MBq) for a time acquisition of 15 min. 11[C]-MET PET/CT images were acquired using two scanners (24 patients on a Siemens scan and 32 patients on a GE scan). Then, LIFEx software was used to delineate brain tumours using two different semi-automatic and user-independent segmentation approaches and to extract 44 radiomics features for each segmentation. A novel mixed descriptive-inferential sequential approach was used to identify a subset of relevant features that correlate with the grading of disease confirmed by pathological examination and clinical outcome. Finally, a machine learning model based on discriminant analysis was used in the evaluation of grading prediction (low grade CNS vs. high-grade CNS) of 11[C]-MET PET/CT. Results: The proposed machine learning model based on (i) two semi-automatic and user-independent segmentation processes, (ii) an innovative feature selection and reduction process, and (iii) the discriminant analysis, showed good performance in the prediction of tumour grade when the volumetric segmentation was used for feature extraction. In this case, the proposed model obtained an accuracy of ~85% (AUC~79%) in the subgroup of patients who underwent Siemens tomography scans, of 80.51% (AUC 65.73%) in patients who underwent GE tomography scans, and of 70.31% (AUC 64.13%) in the whole patients’ dataset (Siemens and GE scans). Conclusions: This preliminary study on the use of an ML model demonstrated to be feasible and able to select radiomics features of 11[C]-MET PET with potential value in prediction of grading of disease. Further studies are needed to improve radiomics algorithms to personalize predictive and prognostic models and potentially support the medical decision process.