Objective <p>The aim of this study was to identify and analyze all the relevant literature regarding the use of machine learning to predict response to neuromodulation therapies in patients diagnosed with drug-resistant epilepsy.</p> Material and methods <p>We systematically search PubMed, Embase, Scopus and Cochrane databases to identify all the studies that used machine learning models to predict response to neuromodulations. Prior to the search, the study was registered at the International prospective register of systematic reviews (PROSPERO, CRD42024543952). Quality assessment and risk of bias was done using PROBAST. A random effects model was used to calculate the pooled value of the AUROC. A sub-analysis was performed for population-specific scenarios.</p> Results <p>A total of 4,451 studies were identified after our initial search, from those, only 12 papers were included in the final analysis. The total number of patients across all the cohorts was 535. 11 studies focused on VNS and only one on ctDCS. Only five out of the 12 studies included an external cohort to validate the results. The most common population was pediatric (<i>n =</i> 7). The most common ML model used was the support vector machine. The pooled area under the receiver operating characteristic curve (AUROC) was 0.84 (95% IC, 079–0.88).</p> Conclusions <p>Our study suggests that multimodal ML approaches show promising performance in predicting response to neuromodulation strategies in patients with drug-resistant epilepsy. However, the limited number of studies, the scarcity of external validation and small cohorts highlight the need for larger, high-quality prospective investigations to confirm these findings and improve the generalizability of ML-based prediction models.</p>