Reactive gliosis is a key feature and an important pathophysiological mechanism underlying chronic neurodegeneration following traumatic brain injury (TBI). In this study, we have explored the effects of intramuscular IGF-1 gene therapy on reactive gliosis and functional outcome after an injury of the cerebral cortex. Young adult male rats were intramuscularly injected with a recombinant adenoviral construct harboring the cDNA of human IGF-1 (RAd-IGF1), with a control vector expressing green fluorescent protein (RAd-GFP) or PBS as control. Three weeks after the intramuscular injections of adenoviral vectors, animals were subjected to a unilateral penetrating brain injury. The data revealed that RAd-IGF1 gene therapy significantly increased serum IGF1 levels and prevent working memory deficits after one week of TBI. At the same time, when we analyzed the effects of therapy on glial scar formation, the treatment with RAd-IGF1 did not modify the number of glial fibrillary acidic protein but we observed a decrease in vimentin immunoreactive astrocytes at 7 days post-lesion in the injured hemisphere, compared to animals treated with RAd-GFP. Moreover, IGF-1 gene therapy reduced the number of Iba1+ cells with reactive phenotype and the number of MHCII+ cells in the injured hemisphere. These results suggest that intramuscular IGF-1 gene therapy may represent a new approach to prevent traumatic brain injury outcomes in rats.