Background: Rhubarb is a traditional Chinese medicine for treating traumatic brain injury (TBI). Purpose: The purpose of this study is to elucidate the potential mechanism of rhubarb by suppressing extracellular signal-regulated kinase (ERK) to ameliorate brain edema. Materials and Methods: Sprague-Dawley rats were separated into four groups at random. One group received 3 g/kg rhubarb, and another group received 12 g/kg rhubarb, and the vehicle group and sham group were administered the same dose of saline solution. The blood–brain barrier disruption and edema were detected by Evans blue extravasation and water content, respectively. ERK, Matrix metalloproteinase 9 (MMP-9), and zonula occluden-1 (ZO-1) in the damaged tissue were measured by western blot analysis and quantitative real-time polymerase chain reaction. Results: Rhubarb attenuated the brain edema after TBI, especially at the dose of 12 g/kg. Rhubarb significantly suppressed ERK, down-regulated MMP-9, and up-regulated ZO-1. Rhubarb might be a prospective therapeutic regimen to decrease edema in TBI. Conclusions: Rhubarb alleviates the edema by restraining the ERK signaling pathway. Our results contribute to the validation of the traditional use of rhubarb in the treatment of TBI and its mechanism.