Despite multimodal treatment, the prognosis of patients with glioblastoma (GBM) remains poor. Previous studies showed conflicting results on the effect of antiepileptic drugs (AED) on GBM survival. We investigated the associations of different AED with overall survival (OS) and progression-free survival (PFS) in a large institutional GBM cohort (n = 872) treated January 2006 and December 2018. In addition, we performed a meta-analysis of previously published studies, including this study, to summarize the evidence on the value of AED for GBM prognosis. Of all perioperatively administered AED, only the use of levetiracetam (LEV) was associated with longer OS (median: 12.8 vs. 8.77 months, p < 0.0001) and PFS (7 vs. 4.5 months, p = 0.001). In the multivariable analysis, LEV was independently associated with longer OS (aHR = 0.74, p = 0.017) and PFS (aHR = 0.68, p = 0.008). In the meta-analysis with 5614 patients from the present and seven previously published studies, outcome benefit for OS (HR = 0.83, p = 0.02) and PFS (HR = 0.77, p = 0.02) in GBM individuals with LEV was confirmed. Perioperative treatment with LEV might improve the prognosis of GBM patients. We recommend a prospective randomized controlled trial addressing the efficacy of LEV in GBM treatment.