Isoflurane is commonly used in experimental traumatic brain injury (TBI), both before and early after injury, yet it is rarely used clinically. Narcotics and benzodiazepines are frequently used after injury in clinical TBI. We compared seven anesthetic/sedative agents applied after injury in the controlled cortical impact model: diazepam, fentanyl, isoflurane, ketamine, morphine, pentobarbital, and propofol. Our objective was to provide insight into the relative degrees of neuroprotection provided by these agents in a standard model of TBI. We hypothesized that the choice of anesthetic/sedative early after experimental TBI critically impacts outcome and that the agents most commonly used clinically may be less neuroprotective than isoflurane. Rats treated with isoflurane had the best cognitive recovery (p < 0.05) and hippocampal neuronal survival (p < 0.05). Conversely, rats treated with ketamine had the most hippocampal neuronal death (p < 0.05). Morphine or propofol, two agents commonly used clinically, were associated with the poorest motor function on post-trauma day 1-5 (p < 0.05). Our data support beneficial effects of isoflurane early after experimental TBI. Our data suggest that the early post-TBI use of isoflurane, despite practical logistical issues, could potentially provide clinical benefits in TBI--versus other commonly used sedatives or analgesics. Furthermore, the choice of post-injury sedation and analgesia could have important implications on attempts to translate novel therapies from bench to field or bedside.