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Hydrogen sulfide (H 2 S), an important endogenous signaling molecule, plays an important neuroprotective role in the central nervous system. However, there is no ideal delivery material or method involving the sustained and controlled release of H 2 S for clinical application in brain diseases. Silk fibroin (SF)-based hydrogels have become a potentially promising strategy for local, controlled, sustained drug release in the treatment of various disorders. Here, we show a silk fibroin (SF)-based hydrogel with sustained H 2 S delivery (H 2 S@SF hydrogel) is effective in treating brain injury through stereotactic orthotopic injection in a severe intracerebral hemorrhage (ICH) mouse model. In this study, we observed H 2 S@SF hydrogel sustained H 2 S release in vitro and in vivo. The physicochemical properties of H 2 S@SF hydrogel were studied using FE-SEM, Raman spectroscopy and Rheological analysis. Treatment with H 2 S@SF hydrogel attenuated brain edema, reduced hemorrhage volume and improved the recovery of neurological deficits after severe ICH following stereotactic orthotopic injection. Double immunofluorescent staining also revealed that H 2 S@SF hydrogel may reduce cell pyroptosis in the striatum, cortex and hippocampus. However, when using endogenous H 2 S production inhibitor AOAA, H 2 S@SF hydrogel could not suppress ICH-induced cell pyroptosis. Hence, the therapeutic effect of the H 2 S@SF hydrogel may be partly the result of the slow-release of H 2 S and/or the effect of the SF hydrogel on the production of endogenous H 2 S. Altogether, the results exhibit promising attributes of injectable silk fibroin hydrogel and the utility of H 2 S-loaded injectable SF hydrogel as an alternative biomaterial toward brain injury treatment for clinical application., (Copyright © 2022 Elsevier B.V. All rights reserved.)