In the ongoing battle between plants and pathogens, plants exhibit a remarkable ability to reprogram their metabolic machinery in defense against pathogen invasion. However, the intricate processes underlying how plants orchestrate metabolic reprogramming to enhance defense responses remain unclear. To address this fundamental question, we employ Bamboo mosaic virus (BaMV) as a model. BaMV, a potexvirus with a single-stranded positive-sense RNA genome, intricately involves various glycolytic enzymes in its replication, and the frequent appearance of mitochondrial clustering around the BaMV replication complex underscores its significance as a model for investigating metabolic-based plant-pathogen interactions. Leveraging a multifaceted omics approach, we delve into BaMV-induced metabolic shifts and their subsequent impact on BaMV propagation. Metabolic profiling reveals an accumulation of hexose phosphates and Krebs cycle intermediates in Nicotiana benthamiana plants upon BaMV infection. Fluxomics uncovers an orchestrated redirection of metabolic flux toward glycolysis and the TCA cycle during BaMV infection. Our proteomics study identifies three mitochondrial proteins with high accumulation in BaMV-infected leaves. Notably, silencing mitochondrial NAD-dependent malic enzyme (NAD-ME1) significantly enhances BaMV accumulation, accompanied by alterations in cytoplasmic NADH-to-NAD ratio and perturbations in defense gene expression. Intriguingly, silencing NAD-ME1 compromises protein accumulation in nonexpresser of PR gene 1 (NPR1). Collectively, our findings underscore the pivotal role of mitochondrial metabolism in governing cytoplasmic redox balance, finely tuning defense systems in response to viral infection.