Ischemic stroke occurs when a clot forms in the cerebrovasculature that starves downstream tissue of oxygen and nutrients resulting in cell death. The tissue immediately downstream of the blockage, the core, dies within minutes, but the surrounding tissue, the penumbra is potentially salvageable. Prostaglandin E2 binds to four different G-protein coupled membrane receptors EP1-EP4 mediating different and sometimes opposing responses. Pharmacological activation of the EP4 receptor has already been established as neuroprotective in stroke, but the mechanism(s) of protection are not well characterized. In this study, we hypothesized that EP4 receptor activation reduces ischemic brain injury by reducing matrix metalloproteinase (MMP)-3/-9 production and blood-brain barrier (BBB) damage. Rats underwent transient ischemic stroke for 90 minutes. Animals received an intravenous injection of either the vehicle or L-902688, a highly specific EP4 agonist, at the onset of reperfusion. Brain tissue was harvested at 24 h. We established a dose-response curve and used the optimal dose that resulted in the greatest infarct reduction to analyze BBB integrity compared to vehicle-treated rats. The presence of IgG, a blood protein, in the brain parenchyma is a marker of BBB damage, and L-902688 (1 mg/kg; i.v.) dramatically reduced IgG extravasation. Consistent with these data, we assessed zona occludens-1, a tight junction protein integral to the maintenance of the BBB, and found it increased with L-902688 administration. With immunoblotting, qRT-PCR, and/or a fluorescence resonance energy transfer (FRET)-based activity assay developed by our group, we next measured MMP-3/-9 since they are key effectors of BBB breakdown in stroke. In the cerebral cortex, not only was MMP-3 activity significantly decreased, but L-902688 treatment also reduced MMP-9 mRNA, protein, and enzymatic activity. In addition, post-ischemic administration of the EP4 agonist significantly reduced pro-inflammatory cytokines IL-1β and IL-6 in the ischemic cortex. Our data show for the first time that pharmacological activation of EP4 with L-902688 is neuroprotective in ischemic stroke by reducing MMP-3/-9 and BBB damage.