Sickness sleep and rebound following sleep deprivation share humoral signals including the rise of cytokines, in particular interleukins. Nevertheless, they represent unique physiological states with unique brain firing patterns and involvement of specific circuitry. Here we performed untargeted metabolomics of mouse cortex and hippocampus to uncover acute changes with sickness and rebound sleep as compared to normal daily sleep. We found that the three states are biochemically unique with larger differences in the cortex than in the hippocampus. Both sickness and rebound sleep shared an increase in tryptophan, with the highest levels during sickness. Surprisingly these two sleep states showed stark differences in terms of the energetic signature, with sickness impinging on glycolysis intermediates whilst rebound increased the triphosphorylated form of nucleotides. These findings indicate that rebound following sleep deprivation stimulates an energy rich state in the brain that is devoid during sickness sleep in line with the energy conservation hypothesis of sickness behavior.