Traumatic brain injury (TBI) has a dramatic impact on our society in terms of mortality, morbidity, and inherently high financial costs. Formidable research efforts are being addressed to the identification of neuroprotective agents capable of ameliorating the neurological outcome after TBI. Preclinical studies have recently demonstrated lithium to be a promising neuroprotective agent for both acute ischemic brain injury and chronic neurodegenerative disease. In light of these encouraging data, we designed a lateral fluid-percussion injury (FPI) study aimed at investigating the role of early post-traumatic administration of lithium as a strategy for reducing TBI-induced motor and cognitive deficits. The optimal dose of this agent and the time window for its administration have been determined on the basis of data derived from the assessment of motor and cognitive functioning in experimental animals, as well as from the stereological quantification of neuronal survival (PID 7) within the CA3 and hilar regions of the hippocampus ipsilateral to the FPI. In addition, we attempted to elucidate the mechanisms underlying the neuroprotective properties of this drug via western blot analysis of levels of the pro-apoptotic marker caspase-3 (PID 1, 7) and two neuroplasticity markers, growth associated protein-43 (GAP-43) and brain-derived neurotrophic factor (BDNF) (PID 1, 7, 21). Our findings indicate that low-dose lithium chloride (0.125 or 0.25 mmol/kg), given either 30 min or 8 hr after lateral FPI significantly ameliorates injury-induced cognitive and motor impairment. Specifically, cell survival in the CA3 region of the hippocampus of the injured lithium-treated animals (but not in the hilus) was significantly increased compared to injured vehicle-treated animals. Western blot analyses revealed a significant increase in GAP-43 levels on PID 7 in injured animals when treated with lithium, indicating a possible mechanism for lithium-induced neuroprotection. In contrast, BDNF levels were relatively unchanged until PID 21, and caspase-3 activation was not observed at all, suggesting that these proteins play less significant roles in the observed neuroprotective effects of lithium treatment after lateral FPI. Early administration of lithium, within 8 hours after TBI, holds promise as an effective therapy to ameliorate postinjury neurobehavioral deficits and warrants further investigation in clinical TBI studies.