Induction of a proinflammatory cytokine, interleukin-1β (IL-1β) plays a role in memory impairment associated with various neurological disorders and brain injury. Here we show that IL-1β-induced memory impairment in brain is mediated by hydrogen sulfide (H2S) synthesized by cystathionine beta-synthase (CBS). H2S modifies GAPDH essentially via sulfhydration in dendrites, which promotes its binding to the E3 ligase protein, Siah. Then Siah binds to a critical synaptic scaffolding molecule, PSD95, and leads it to degradation via ubiquitination. In CBS heterozygous mice (cbs(+/-)) and primary neurons depleted with either CBS or IL-1R, IL-1β-induced loss of PSD95 was rescued along with a decrease in the level of GAPDH sulfhydration. Moreover, decrease in the loss of PSD95 in cbs(+/-) mice results in improvement of IL-1β-induced cognitive deficits and neurobehavioral outcomes. Thus, our findings reveal a mechanism where GAPDH sulfhydration appears to be a physiologic determinant of cytokine-induced memory impairment in brain.