Translational stroke studies, in particular those involving animal modeling, are greatly needed to safely integrate basic preclinical investigations ahead of eventual clinical applications [21–25]. This study therefore investigated the value of modulating thrombin–PAR-1 and PAR-4 with reversing COX-2 upregulation, as well as the effect of direct COX-2 inhibition on post-hemorrhagic hydrocephalus and on neurological deficits. In prior studies, others hypothesized that hydrocephalus mechanisms involved increased production of infiltrating extracellular matrix (ECM) proteins throughout the cerebroventricular system and that these would lead to the obstruction of CSF outflow [1, 2, 10, 14, 15, 26–30]. Our data suggest that thrombin-induced PAR-1, -4 stimulation could upregulate harmful signaling, exacerbating inflammatory signaling (i.e., COX-2 mediated) upstream of ECM dysregulation [1, 8, 12, 14, 15, 31–34]. Thus, we hypothesized that thrombin binding to PAR-1, -4 receptors could consequently upregulate COX-2 protein. Furthermore, we investigated inhibition of PAR-1, -4 using a combined treatment with SCH79797 (PAR-1 antagonist) and p4pal10 (PAR-4 antagonist), which also significantly improved COX-2 after 72 h. Next, we asked whether directly inhibiting COX-2 following GMH could circumvent long-term negative outcomes. Our findings demonstrated that vehicle-treated animals had significantly worsened outcomes compared with shams, and treatment with NS398 (COX-2 inhibitor) significantly improved not only neuropathology but also and neurological ability. Therefore, by decreasing the early inflammatory COX-2 signaling pathway, we improved long-term outcome in juvenile animals. In summary, this study is the first to show that normalization of thrombin–PAR-1, -4 signals positively affect early COX-2 expression levels and improve long-term outcomes following collagenase infusion-mediated GMH.