Background Comprehensive data on the efficacy and tolerability of AED treatment in glioma patients with epilepsy is currently lacking. In this systematic review we specifically assessed the efficacy of AEDs in patients with a grade II-IV glioma. Methods Electronic databases PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane library were searched up to June 2020. Three different outcomes for both mono- and polytherapy were extracted from all eligible articles: (I) seizure freedom; (II) ≥50% reduction in seizure frequency; and (III) treatment failure. Weighted averages (WA) were calculated for outcomes at 6 and 12 months. Results A total of 66 studies were included. Regarding the individual outcomes on the efficacy of monotherapy, the highest seizure freedom rate at 6 months was with phenytoin (WA=72%) while at 12 months pregabalin (WA=75%) and levetiracetam (WA=74%) showed highest efficacy. Concerning ≥50% seizure reduction rates, levetiracetam showed highest efficacy at 6 and 12 months (WAs of 82% and 97%, respectively). However, treatment failure rates at 12 months were highest for phenytoin (WA=34%) and pregabalin (41%). When comparing the described polytherapy combinations with follow-up of ≥6 months, levetiracetam combined with phenytoin was most effective followed by levetiracetam combined with valproic acid. Conclusion Given the heterogeneous patient populations and the low scientific quality across the different studies, seizure rates need to be interpreted with caution. Based on the current limited evidence, with the ranking of AEDs being confined to the AEDs studied, levetiracetam, phenytoin and pregabalin seem to be most effective as AED monotherapy in glioma patients with epilepsy, with levetiracetam showing the lowest treatment failure rate, compared to the other AEDs studied.