Traumatic　brain　injury　(TBI)　is　a　major　cause　of　mortality　and　disability　worldwide.　To　date,　therapies　to　treat　any　forms　of　TBI　are　still　limited.　Recent　studies　have　demonstrated　the　potential　neuroprotective　effects　of　molecular　hydrogen　on　TBI.　Although　it　has　been　demonstrated　that　hydrogen　inhalation　(HI)　for　about　5　hrs　immediately　after　TBI　has　a　beneficial　effect　on　brain　injury,　the　most　effective　intervention　procedure　in　the　treatment　of　TBI　remains　unknown.　The　mechanism　underlying　the　neuroprotective　effects　of　HI　on　TBI　also　needs　to　be　further　investigated.　Our　results　showed　that　inhalation　of　4%　hydrogen　during　the　first　day　after　TBI　was　the　most　effective　hydrogen　intervention　procedure　in　the　treatment　of　TBI.　Pathological　examination　showed　that　HI　could　attenuate　TBI-induced　reactive　astrocytosis　and　microglial　activation.　Nissl　staining　demonstrated　a　significant　decrease　in　the　number　of　nissl-stained　dark　neurons　(N-DNs)　in　HI　group　compared　to　TBI　group　at　2　h　post-TBI,　and　the　TBI-induced　neuronal　loss　was　attenuated　by　HI　at　day　3　post-TBI.　IHC　staining　showed　that　HI　resulted　a　decrease　in　CD16-positive　cells　and　a　further　increase　in　CD206-positive　cells　as　compared　to　TBI　group.　Multiplex　cytokine　assay　demonstrated　the　most　profound　regulatory　effects　induced　by　HI　on　the　levels　of　IL-12,　IFN-gamma,　and　GM-CSF　at　24　h　post-TBI,　which　confirmed　the　inhibitory　effect　of　hydrogen　on　microglia　activation.　We　concluded　that　inhalation　of　4%　hydrogen　during　the　first　day　after　TBI　was　the　most　effective　intervention　procedure　in　the　treatment　of　TBI.　Our　results　also　showed　that　hydrogen　may　exert　its　protective　effects　on　TBI　via　inhibition　of　microglia　activation　and　neuroinflammation.