Introduction: Drug-resistant epilepsy (DRE) poses significant challenges in pediatric neurology . The ketogenic diet (KD) shows clinical efficacy , yet its molecular mechanisms remain unclear. This study investigated KD\\\'s metabolic regulatory mechanisms through multi-omics analysis. Objective: To evaluate KD\\\'s clinical efficacy and safety in pediatric DRE and elucidate itsmetabolic mechanisms through lipidomics and proteomics integration. Methods: A total of 206 DRE children were enrolled, with 28 undergoing proteomic and lipidomicanalyses before and after 6-month KD treatment, compared with 21 healthy controls. Clinical outcomes, differential proteins, and lipid metabolites were analyzed. Results: KD achieved higher seizure control (50.5% vs 37 .9%, P=0.03) and EEG improvement (45.7% vs 29.2%, P=0.04) than conventional treatment, with better neurodevelopment in ages 0-8 years. Proteomics identified 284 differential proteins pre-KD, reducing to 29 post-KD, with reversed trends in oxidative phosphorylation.