Hydrogen sulfide (H2S), a well-known endogenous mediator, has been shown to exert protective effects against neuronal damage caused by brain ischemia, but the mechanism of its action remains unclear. We have reported the neuroprotective properties of H2S against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury by inhibiting the phosphorylation of p38. The present study evaluates the effect of H2S on OGD/R-induced cell injury or apoptosis and the mechanisms for its action in PC12 cells. Pretreatment of PC12 cells with exogenous sodium hydrosulfide (NaHS) (a H2S donor, 100 or 300 µM) for 12 h before exposure to OGD/R markedly attenuated p38 phosphorylation. Activation of p38 MAPK by transfection of activated p38α, but not p38β, reversed the protective effect of NaHS, as measured by enzyme-linked immunosorbent assay analysis. Importantly, SB203580 (a p38 MAPK inhibitor) also reversed the protective effects of p38α-activated p38 MAPK. Interleukin-6 secretion after OGD/R decreased significantly with NaHS compared with without NaHS. Taken together, we show that the p38 pathway contributes toward OGD/R-induced cell death and p38α plays a key role in OGD/R-induced interleukin-6 secretion.