We aimed to use quantitative values derived from perfusion and diffusion-weighted MR imaging (PWI and DWI) to differentiate radiation-induced necrosis (RIN) from tumor recurrence in Glioblastoma (GBM) and investigate the best parameters for improved diagnostic accuracy and clinical decision-making. Methods: A retrospective analysis of follow-up MRI with new enhancing observations was performed in histopathologically confirmed subjects of post-treated GBM, who underwent re-surgical exploration. Quantitative estimation of rCBV (relative cerebral blood volume) from PWI and three methods of apparent diffusion coefficient (ADC) estimation were performed, namely ADC R1 (whole cross-sectional area of tumor), ADC R2 (only solid enhancing lesion), and ADC R3 (central necrosis). ROC curve and logistic regression analysis was completed. A confusion matrix table created using Excel provided the best combination parameters to ameliorate false-positive and false-negative results. Results: Forty-four subjects with a mean age of 46 years (range, 19–70 years) underwent re-surgical exploration with RIN in 28 (67%) and recurrent tumor in 16 (33%) on histopathology. rCBV threshold of >3.4 had the best diagnostic accuracy (AUC = 0.93, 81% sensitivity and 89% specificity). A multiple logistic regression model showed significant contributions from rCBV (p < 0.001) and ADC R3 (p = 0.001). After analysis of confusion matrix ADC R3 > 2032 × 10⁻⁶ mm² achieved 100% specificity with gain in sensitivity (94% vs. 56%). Conclusions: A combination of parameters had better diagnostic performance, and a stepwise combination of rCBV and ADC R3 obviated unnecessary biopsies in 10% (3/28), leading to improved clinical decision-making.