Despite the robust diagnostic performance of MRI-based radiomic features for differentiating between glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL) reported on prior studies, the best sequence or a combination of sequences and model performance across various machine learning pipelines remain undefined. Herein, we compare the diagnostic performance of multiple radiomics-based models to differentiate GBM from PCNSL. Our retrospective study included 94 patients (34 with PCNSL and 60 with GBM). Model performance was assessed using various MRI sequences across 45 possible model and feature selection combinations for nine different sequence permutations. Predictive performance was assessed using fivefold repeated cross-validation with five repeats. The best and worst performing models were compared to assess differences in performance. The predictive performance, both using individual and a combination of sequences, was fairly robust across multiple top performing models (AUC 0.961–0.977) but did show considerable variation between the best and worst performing models. The top performing individual sequences had comparable performance to multiparametric models. The best prediction model in our study used a combination of ADC, FLAIR, and T1-CE achieving the highest AUC of 0.977, while the second ranked model used T1-CE and ADC, achieving a cross-validated AUC of 0.975. Radiomics-based predictive accuracy can vary considerably, based on the model and feature selection methods as well as the combination of sequences used. Also, models derived from limited sequences show performance comparable to those derived from all five sequences.