Evidence of injury-induced neurogenesis in the adult hippocampus suggests that an endogenous repair mechanism exists for cognitive dysfunction following traumatic brain injury (TBI). One factor that may be associated with this restoration is S100B, a neurotrophic/mitogenic protein produced by astrocytes, which has been shown to improve memory function. Therefore, we examined whether an intraventricular S100B infusion enhances neurogenesis within the hippocampus following experimental TBI and whether the biological response can be associated with a measurable cognitive improvement. Following lateral fluid percussion or sham injury in male rats (n = 60), we infused S100B (50 ng/h) or vehicle into the lateral ventricle for 7 days using an osmotic micro-pump. Cell proliferation was assessed by injecting the mitotic marker bromodeoxyuridine (BrdU) on day 2 postinjury. Quantification of BrdU-immunoreactive cells in the dentate gyrus revealed an S100B-enhanced proliferation as assessed on day 5 post-injury (p < 0.05), persisting up to 5 weeks (p < 0.05). Using cell-specific markers, we determined the relative numbers of these progenitor cells that became neurons or glia and found that S100B profoundly increased hippocampal neurogenesis 5 weeks after TBI (p < 0.05). Furthermore, spatial learning ability, as assessed by the Morris water maze on day 30-34 post-injury, revealed an improved cognitive performance after S100B infusion (p < 0.05). Collectively, our findings indicate that an intraventricular S100B infusion induces neurogenesis within the hippocampus, which can be associated with an enhanced cognitive function following experimental TBI. These observations provide compelling evidence for the therapeutic potential of S100B in improving functional recovery following TBI.