Simple Summary: Although the incidence of glioblastoma (GB) in people over 65 years is more than twice as high as in younger people, no standard of care for the treatment of the elderly with GB has been established so far. With this study, we aimed to investigate the predictors affecting outcomes in elderly GB patients with regard to their overall survival (OS) and progression-free survival (PFS). MGMT promoter methylation, gross total resection (GTR), and hypofractionated radiation were associated with a longer OS in elderly glioblastoma patients. These findings may induce the optimization of the treatment regimen for elderly patients that has not yet been established. (1) Background: Although the incidence of glioblastoma (GB) has a peak in patients aged 75–84 years, no standard treatment regimen for elderly patients has been established so far. The goal of this study was to analyze the outcome of GB patients ≥ 65 years to detect predictors with relevant impacts on overall survival (OS) and progression-free survival (PFS). (2) Methods: Medical records referred to our institution from 2006 to 2020 were analyzed. Adult GB patients with clinical data, postoperative MRI data, and ≥1 follow-up investigation after surgical resection were included. The complete cohort was divided into a younger (<65) and an elderly group (≥65 years). Multiple factors regarding OS and PFS were scanned using univariate and multivariable regression with p < 0.05. (3) Results: 1004 patients were included with 322 (61.0%) male individuals in the younger and 267 (56.1%) males in the older cohort. The most common tumor localization was frontal in both groups. Gross total resection (GTR) was the most common surgical procedure in both groups, followed by subtotal resection (STR) (145; 27.5%) in the younger group, and biopsy (156; 32.8%) in the elderly group. Multivariate analyses detected that in the younger cohort, MGMT promoter methylation and GTR were predictors for a longer OS, while MGMT methylation, GTR, and hypofractionated radiation were significantly associated with a longer OS in the elderly group. (4) Conclusions: Elderly patients benefit from surgical resection of GB when they show MGMT promoter methylation, undergo GTR, and receive hypofractionated radiation. Furthermore, MGMT methylation seems to be associated with a longer PFS in elderly patients. Further investigations are required to confirm these findings, especially within prospective radiation therapy studies and molecular examinations. [ABSTRACT FROM AUTHOR]