Depletion of glutathione (GSH) is considered a critical pathogenic event promoting alcohol-induced lipotoxicity. We recently show that systemic GSH deficiency in mice harboring a global disruption of the glutamate-cysteine ligase modifier subunit (Gclm) gene confers protection against alcohol-induced steatosis. While several molecular pathways have been linked to the observed hepatic protection, including nuclear factor erythroid 2-related factor 2 and AMP-activated protein kinase pathways, the precise mechanisms are yet to be defined. In this study, to gain insights into the molecular mechanisms underpinning the protective effects of loss of GCLM, global profiling of hepatic polar metabolites combined with liver microarray analysis was carried out. These inter-omics analyses revealed both low GSH- and alcohol-driven changes in multiple cellular pathways involving the metabolism of amino acids, fatty acid, glucose and nucleic acids. Notably, several metabolic changes were uniquely present in alcohol-treated Gclm-null mouse livers, including acetyl-CoA enrichment and diversion of acetyl-CoA flux from lipogenesis to alterative metabolic pathways, elevation in glutamate concentration, and induction of the glucuronate pathway and nucleotide biosynthesis. These metabolic features reflect low GSH-elicited cellular response to chronic alcohol exposure, which is beneficial for the maintenance of hepatic redox and metabolic homeostasis. The current study indicates that fine-tuning of hepatic GSH pool may evoke metabolic reprogramming to cope with alcohol-induced cellular stress.