Background: Drug-resistant epilepsy (DRE) can affect up to one third of individuals with epilepsy. We conducted a systematic review and meta-analysis of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) in patients with DRE to summarize the current evidence on efficacy and tolerability for these neuromodulation modalities. Methods: We searched three online databases with a pre-specified search strategy. We included published randomized controlled trials (RCT) and their open-label extension studies, as well as prospective case series, with samples greater than 20 participants, reporting efficacy and tolerability. Results: We identified 31 studies, six of which are RCTs and 25 prospective observational studies. At long term follow-up, five observational studies for VNS reported a pooled mean decrease in seizure frequency at last follow-up of 35%. In the extension studies for RNS, the median seizure reduction was 53%, 66% and 75.0% at two, five and nine years respectively. For DBS, the median reduction was then 56%, 69% and 75% at two, five and seven years respectively. Conclusions: Neurostimulation modalities are effective for the treatment of DRE, with improving outcomes over time and few major complications. Higher quality long-term data on DBS and RNS suggest larger seizure reduction rates than VNS.