Akt and mammalian target of rapamycin (mTOR) are both activated after traumatic brain injury (TBI), however complex interplay between the two hampers deciphering their functional implications in vivo. We examined the effects of single and combination inhibitors of Akt/mTOR in a mouse controlled cortical impact (CCI) model. Following CCI, phospho-Akt-473 (p-Akt) and -S6 ribosomal protein (p-S6RP), a downstream substrate of mTOR, were increased in cortical and hippocampal brain homogenates (P<0.05 versus sham). At 24 hours, p-S6RP was detected in neurons and was robustly induced in microglia and astrocytes in injured hippocampus. In vivo activity of Akt and mTOR inhibitors administered separately was confirmed by reduced expression of p-GSK3β (P<0.01) or p-S6RP (P<0.05), respectively, after CCI. Importantly, administration of Akt and mTOR inhibitors together (but not of either alone) improved postinjury motor (P=0.02) and cognitive deficits (hidden platform trials, P=0.001; probe trials, P<0.05), decreased propidium iodide-positive cells in CA1 and CA3 (P<0.005), and unexpectedly increased p-GSK3β in hippocampus. Although the roles of Akt and mTOR in the pathogenesis of TBI remain to be fully elucidated, dual inhibition of Akt and mTOR may have therapeutic potential for TBI.