As a severe neurological disease of trauma, traumatic brain injury (TBI) leads to other disorders, such as depression, dementia and epilepsy. This study investigated whether poly d,l-(lactic-co-glycolic) acid (PLGA) PEGylated isoliquiritigenin could alleviate TBI. One hundred and eighty-three patients with clinical brain trauma were divided into two groups with or without intracranial injury in magnetic resonance imaging. The clinical results showed that serum cyclooxygenase 2 (COX-2) levels were obviously increased in the TBI patients compared to the patients with head trauma only or healthy individuals. Intracranial injection of isoliquiritigenin in TBI rats reversed TBI induced increase of COX-2 level, significantly reduced water content and contusion volume. Our findings suggest that PLGA PEG nanoparticles loaded with isoliquiritigenin can achieve the same effects as intracranial administration of isoliquiritigenin in reducing serum COX-2 level.