AbstractTraumatic brain injury (TBI) can have long‐lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo‐Dex were well tolerated in human and murine neural cells. Lipo‐Dex showed significant suppression of inflammatory cytokines, IL‐6 and TNF‐α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo‐Dex were administered to young adult male and female C57BL/6 mice immediately after controlled cortical impact injury (a TBI model). Our findings demonstrate that Lipo‐Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of pro‐inflammatory cytokines, and microglial activation compared to Lipo‐treated mice in a sex‐dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano‐therapies for brain injury. These results suggest that Lipo‐Dex administration may effectively treat acute TBI.