The study aims to evaluate the efficacy of neuromodulatory strategies for people who have drug-resistant epilepsy (DRE).We searched electronic repositories, including PubMed, Web of Science, Embase, and the Cochrane Library, for randomised controlled trials, their ensuing open-label extension studies, and prospective studies focusing on surgical or neuromodulation interventions for people with DRE. We used seizure frequency reduction as the primary outcome. A single-arm meta-analysis synthesised data across all studies to assess treatment effectiveness at multiple time points. A network meta-analysis evaluated the efficacy of diverse therapies in RCTs. GRADE was applied to evaluate the overall quality of the evidence.Twenty-eight studies representing 2936 individuals underwent ten treatments were included. Based on the cumulative ranking in the network meta-analysis, the top three neuromodulatory options were deep brain stimulation (DBS) with 27% probability, responsive neurostimulation (RNS) with 22.91%, and transcranial direct current stimulation with 24.31%. In the single-arm meta-analysis, in the short-to-medium term, seizure control is more effective with RNS than with vagus nerve stimulation (inVNS), which in turn is slightly more effective than DBS, though the differences are minimal. However, in the long term, inVNS appears to be less effective than both DBS and RNS. Trigeminal nerve stimulation, transcranial magnetic stimulation, and transcranial alternating current stimulation did not demonstrate significant seizure frequency reduction.Regarding long-term efficacy, RNS and DBS outperformed inVNS. While transcranial direct current stimulation and transcutaneous auricular VNS showed promise for treating DRE, further studies are needed to confirm their long-term efficacy.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.