Imbalance of oxidative and inflammatory regulation is the main contributor to neurofunctional deterioration and failure of rebuilding spared neural networks after spinal cord injury (SCI). As an emerging bio-safe strategy for protecting against oxidative and inflammatory damage, hydrogen (H-2) therapy is a promising approach for improving the microenvironment to allow neural regeneration. However, achieving release of H-2 at sufficient concentrations specifically into the injured area is critical for the therapeutic effect of H-2. Thus, we assembled SiO2@mSiO(2) mesoporous silica nanoparticles and loaded them with ammonia borane (AB), which has abundant capacity and allows controllable release of H-2 in an acid-dependent manner. The release of H-2 from AB/SiO2@mSiO(2) was satisfactory at pH 6.6, which is approximately equal to the microenvironmental acidity after SCI. After AB/SiO2@mSiO(2) were intrathecally administered to rat models of SCI, continuous release of H-2 from these nanoparticles synergistically enhanced neurofunctional recovery, reduced fibrotic scar formation and promoted neural regeneration by suppressing oxidative stress reaction. Furthermore, in the subacute phase of SCI, microglia were markedly polarized toward the M2 phenotype by H-2 via inhibition of TLR9 expression in astrocytes. In conclusion, H2 delivery through AB/SiO2@mSiO(2) has the potential to efficiently treat SCI through comprehensive modulation of the oxidative and inflammatory imbalance in the microenvironment.