Leukemia inhibitory factor (LIF) is a neuroprotective cytokine that is essential for appropriate glial responses, remyelination, and preservation of neuronal conductance after injury. The intranasal route for delivery of therapeutics to the central nervous system is of particular interest given that it bypasses the blood–brain barrier and peripheral clearance systems. We explored the possibility that LIF might improve neurological function when administered intranasally during the acute phase in a pediatric model of mild traumatic brain injury (mTBI). We tested two doses of LIF and evaluated behavioral outcomes. Here, we show that acute 40-ng intranasal LIF treatment twice a day for 3 days attenuates astrogliosis and microgliosis, protects against axonal damage, significantly improves sensorimotor function, and is well tolerated without detrimental effects on growth. Altogether, our studies provide pre-clinical evidence for the use of acute intranasal LIF treatment as a viable therapeutic for pediatric cases of mTBIs.