Although the adult brain primarily metabolizes glucose, the evidence from the starvation literature has demonstrated that the adult brain retains some potential to revert to ketone metabolism. This attribute has been exploited recently to shift the adult brain toward ketone metabolism after traumatic brain injury (TBI), resulting in increased cerebral uptake and oxidation of exogenously administered ketones and improved cerebral energy. The ability to utilize ketones as an alternative substrate decreases with cerebral maturation, suggesting that the younger brain has a greater ability to metabolize this substrate and may be more receptive to this therapy. It was hypothesized that the administration of ketones after TBI in the developing brain will decrease lesion size in an age-dependent manner. Postnatal day (PND) 17, 35, 45, and 65 rats were placed on either a standard or ketogenic (KG) diet after controlled cortical impact (CCI) injury. PND35 and PND45 KG-fed animals showed a 58% and 39% reduction in cortical contusion volume, respectively, at 7 days post-injury. The KG diet had no effect on contusion volume in PND17 and PND65 injured rats. Both PND35 and PND45 KG-fed groups revealed fewer Fluoro-Jade–positive cells in the cortex and hippocampus at 6 hr and showed earlier decreases in plasma lactate compared to standard-fed animals. The age-dependent ketogenic neuroprotection is likely related to age-related differences in cerebral metabolism of ketones and suggests that alternative substrate therapy has potential applications for younger head-injured patients. © 2005 Wiley-Liss, Inc.