Metabolic resistance is commonly attributed to the overexpression of detoxification enzymes, whereas the metabolic systems that sustain detoxification remain less well resolved. Here, we integrated widely targeted metabolomics and transcriptomics to compare the clothianidin-resistant brown planthopper strain CLR with the susceptible strain CLS and validated candidate genes in an independent nitenpyram-resistant background. CLR and CLS exhibited distinct metabolomic profiles. Differential genes and metabolites converged on carbon metabolism, glycolysis/gluconeogenesis, the tricarboxylic acid cycle, glutathione metabolism, pentose and glucuronate interconversions, cytochrome P450-mediated xenobiotic metabolism, and ABC transporters. These changes were summarized into four interconnected modules involving glycolytic energy supply, protective sugar-derived metabolites, pyruvate–TCA–malate metabolism, and UGT-mediated glycosylation. Expression analysis identified a mitochondrial NADP-dependent isocitrate dehydrogenase gene and UDP-glucosyltransferase 2 (UGT2) as consistently upregulated in both resistant backgrounds. Silencing NADP reduced the LC₅₀ of nitenpyram and clothianidin by 1.84- and approximately 1.81-fold, respectively, whereas UGT2 silencing produced corresponding reductions of 1.89- and 1.83-fold. These findings indicate that neonicotinoid resistance in Nilaparvata lugens is supported by coordinated remodelling of central metabolism and detoxification and identify two candidate metabolic nodes for further resistance management research.