Recent trials have shown that the prostaglandin E2 EP1 receptor is responsible for NMDA excitotoxicity in the brain after injury. Consequently, in this study, we investigated the use of SC-51089, a selective prostaglandin E2 EP1 receptor antagonist, as a pre-treatment modality to decrease cell death, reduce brain edema, and improve neurobehavioral function after surgically induced brain injury (SBI) in mice. Eleven-week-old C57 black mice (n = 82) were randomly assigned to four groups: sham (n = 31), SBI (n = 27), SBI treated with SC51089 at 10 μg/kg (n = 7), and SBI treated with SC51089 at 100 μg/kg (n = 17). Treated groups received a single dose of SC51089 intrapertioneally at 12 and 1 h pre-surgery. SBI was performed by resecting the right frontal lobe using a frontal craniotomy. Postoperative assessment occurred at 24 and 72 h, and included neurobehavioral testing and measurement of brain water content and cell death. Results indicated that neither low-nor high-dose EP1 receptor inhibition protected against the SBI-related effects on brain edema formation or cell death. There was however a significant improvement in neurobehavioral function 24 h post-SBI with both dosing regimens. Further studies will be needed to assess the potential therapeutic role of EP1 receptor targeting in SBI.