Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remains a leading cause of preventable death worldwide. Mesenchymal stem cell-derived exosomes have demonstrated promise in small animal models of neurologic injury. To investigate the effects of exosome treatment in a clinically realistic large animal model, Yorkshire swine were subjected to TBI and HS. Animals were maintained in shock for 2 hours prior to resuscitation with normal saline (NS). Animals were then either resuscitated with NS (3 x volume of shed blood) or with the same volume of NS with delayed exosome administration (1×1013 particles/4ml) (n=5/cohort). Exosomes were administered 9 hours post-injury, and on post-injury days (PID) 1, 5, 9, and 13. Neurologic severity scores (NSS) were assessed for 30 days, and neurocognitive functions were objectively measured. Exosome-treated animals had significantly lower NSS (p < 0.05) during the first 5 days of recovery. Exosome-treated animals also had a significantly shorter time to complete neurologic recovery (NSS = 0) compared to animals given NS alone (days to recovery: NS = 16.8 ± 10.6; NS + exosomes = 5.6 ± 2.8; p = 0.03). Animals treated with exosomes initiated neurocognitive testing earlier (days to initiation: NS = 9.6 ± 0.5 vs. NS + exosomes = 4.2 ± 0.8; p = 0.008), however no difference was seen in time to mastery of tasks. In conclusion, treatment with exosomes attenuates the severity of neurologic injury and allows for faster neurologic recovery in a clinically realistic large animal model of TBI and HS.