Translational stroke studies, in particular those involving animal modeling, are greatly needed to safely integrate basic preclinical investigations ahead of eventual clinical applications [22–26]. This study therefore investigated the modulation of thrombin–PAR-1 and PAR-4 in reversing p-mTOR upregulation, as well as the effect of direct p-mTOR inhibition on neurological deficits. Prior studies hypothesized mechanisms of hydrocephalus involving increased production of infiltrating extracellular matrix (ECM) proteins of the cerebroventricular system, thus leading to the disruption of cerebrospinal fluid (CSF) outflow [1, 2, 14, 15, 27–32]. Our results suggested that thrombin-induced PAR-1,-4 stimulation could upregulate detrimental proliferative responses (i.e., p-mTOR mediated), possibly upstream of ECM dysregulation [1, 8, 11, 14, 15, 33–35]. To address the question of molecular mediators, we demonstrated that intraparenchymal infusion of collagenase generated thrombin with greatest activity in the acute phase between 6 and 24 h post-GMH, and then hypothesized that thrombin binds to PAR-1, -4 receptors, consequently upregulating p-mTOR. Because thrombin is most active in the early time frame, we examined levels at 72 h after GMH and found that p-mTOR was significantly greater in vehicle animals compared with shams. Then, inhibiting PAR-1, -4 through combined therapy using SCH-79797 (PAR-1 antagonist) and p4pal10 (PAR-4 antagonist) significantly ameliorated p-mTOR by day 3 after GMH. We then asked whether direct inhibition of p-mTOR could improve long-term outcome. Our findings showed that vehicle-treated animals significantly worsened outcome compared with shams, and treating with rapamycin (mTOR inhibitor) could significantly improve neurological ability. Thus, by decreasing early proliferative (i.e., p-mTOR) signaling, we improved long-term juvenile outcome. In sum, this study showed that thrombin-PAR-1, -4 signal inhibitions normalized early p-mTOR expression, and may improve long-term GMH outcome.