Activation of protease-activated receptors (PARs) is known to exert neuroprotection when low concentrations of the agonist protease thrombin are applied. However, the mechanism of protection is still unclear. Here, we showed that activation of multiple PARs, including PAR-1, PAR-2 and PAR-4, was able to elevate the release of the chemokine cytokine-induced neutrophil chemoattractant (CINC)-3 from rat astrocytes, in addition to evoking CINC-1 secretion. Different molecular mechanisms were identified as being involved in the secretion of CINC-1 and CINC-3, upon activation of different PARs. Importantly, we found that both CINC-1 and CINC-3 could signal to rat cortical neurons. Both chemokines acted via CXCR2 to prevent C2-ceramide-induced cytochrome c release from mitochondria. Consequently CINC-1 and CINC-3 protected neurons from apoptosis. We further revealed that conditioned media obtained from PAR-activated astrocytes similarly protected cortical neurons against C2-ceramide-induced cell death. The neuroprotection was considerably suppressed by a CXCR2 antagonist. CXCR2 is the cognate receptor for CINC. Therefore, our findings demonstrate that PAR-activated astrocytes are able to protect neurons against neurodegeneration and cell death via regulation of the secretion of chemokines CINC-1 and CINC-3. These data indicate a previously unknown mechanism for astrocyte-mediated neuroprotection achieved by PAR activation.