Kirsten rat sarcoma virus (KRAS) oncogene, found in 20%–25% of lung cancer patients, potentially regulates metabolic reprogramming and redox status during tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS‐mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2‐related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS‐mutant human lung cancer. LC‐MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS‐mutant H358 non‐small cell lung cancer cells. Furthermore, l‐methionine (methyl‐13C) isotope tracer was used to explore the effect of belinostat on one‐carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE‐NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2‐C8 cells (containing pARE‐TI‐luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS‐mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α‐ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino‐succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. 13C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2‐regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS‐mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.