Heart failure is a leading cause of mortality worldwide. The failing heart undergoes profound metabolic changes, but a comprehensive evaluation in humans is lacking. We integrate here plasma and cardiac tissue metabolomics of 678 metabolites, genome-wide RNA-seq, and global proteomic studies, to examine metabolic status in 87 explanted human hearts from 39 patients with end-stage heart failure compared to 48 non-failing donors. The data confirm a bioenergetic defect in end-stage human heart failure and reveal a selective depletion of adenylate purines (but not guanylates or pyrimidines), required for maintaining levels of ATP. We observe substantial reductions in fatty acids (FA) and acyl-carnitines in failing tissue, despite elevations in plasma, suggesting defective import of FAs into cardiomyocytes. Glucose levels, in contrast, are elevated in failing hearts. Downstream intermediates of glycolysis, pentose phosphate pathway, and glycogen synthesis are reduced, suggesting some blend of upstream bottleneck of glucose phosphorylation or accelerated downstream consumption. Notably, the key enzyme that gates carbohydrate oxidation by the TCA cycle, pyruvate dehydrogenase, is de-repressed, allowing increased lactate and pyruvate burning. TCA intermediates are significantly reduced in failing hearts, perhaps due to shunting of pyruvate towards oxidation. Finally, the bioactive lipid content of failing human hearts is profoundly reprogrammed, with marked reductions in ceramides and elevations in nearly all lysoglycerophospholipids species. Together, these data show profound metabolic and lipid abnormalities in human failing hearts and provide insight into mechanisms contributing to the bioenergetic defect of failing hearts.