Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications.