Children who suffered traumatic brain injury (TBI) often experience acute and chronic pain, which is linked to a poor quality of life. Buprenorphine (BPN) is commonly used to treat moderate to severe persistent pain in children, however, the efficacy and safety profile of BPN in the pediatric population is still inconclusive. This study investigated the sex-specific effects of BPN on body weight, motor coordination and strength, expression of opioid receptors in the white matter astrocytes, and neuroinflammation in a mouse impact acceleration model of pediatric TBI. Male and female littermates were randomized on postnatal day 20-21(P20-21) into Sham, TBI + saline and TBI + BPN groups. Mice in the TBI + saline and TBI + BPN groups underwent TBI, while the Sham group underwent anesthesia without injury. BPN (0.075 mg/kg) was administered to the TBI + BPN mice at 30 min after injury, and then every 6-12 h for 2 days. Mice in the TBI + saline group received the same amount of saline injections. The impact of BPN on body weight, motor function, opioid receptor expression, and neuroinflammation was evaluated at 1-day (d), 3-d and 7-d post-injury. We found that 1) TBI induced significant weight loss in both males and females. BPN treatment improved weight loss at 3-d post-injury in females. 2) TBI significantly impaired motor coordination and strength. BPN improved motor coordination and strength in both males and females at 1-d and 3-d post-injury. 3) TBI significantly decreased exploration activity at 1-d post-injury in males, and at 7-d post-injury in females, while BPN improved the exploration activity in females. 4) TBI significantly increased mRNA expression of mu-opioid receptors (MOR) at 7-d post-injury in males, but decreased mRNA expression of MOR at 1-d post-injury in females. BPN normalized MOR mRNA expression at 1-d post-injury in females. 5) MOR expression in astrocytes at corpus callosum significantly increased at 7-d post-injury in male TBI group, but significantly decreased at 1-d post-injury in female TBI group. BPN normalized MOR expression in both males and females. 6) TBI significantly increased the mRNA expression of TNF-α, IL-1β, IL-6 and iNOS. BPN decreased mRNA expression of iNOS, and increased mRNA expression of TGF-β1. In conclusion, this study elucidates the sex specific effects of BPN during the acute phase after pediatric TBI, which provides the rationale to assess potential effects of BPN on chronic pathological progressions after pediatric TBI in both males and females.