Therapeutic drug development for central nervous system injuries, such as traumatic brain injury (TBI), presents significant challenges. TBI results in primary mechanical damage followed by secondary injury, leading to cognitive dysfunction and memory loss. Our recent study demonstrated the potential of carbon monoxide-releasing molecules (CORMs) to improve TBI recovery by enhancing neurogenesis. However, a comprehensive TBI recovery strategy requires not only neurogenesis but also oligodendrogenesis. In this study, we elucidate the critical role of A-kinase anchor protein 12 (AKAP12), a scaffolding protein predominantly expressed by intact pericytes, in oligodendrocyte regeneration during CO therapy for TBI. CORM treatment increased AKAP12 expression, which enhanced myelin intensity and mitigated TBI-induced oligodendrocyte loss. In addition, CO promotes the generation of new oligodendrocytes, a process that is impaired by AKAP12 deficiency. Notably, even after TBI, cognitive function was restored in wild-type mice following CORM treatment, but this effect was absent in Akap12 knockout mice. These findings highlight the importance of CO-induced AKAP12 upregulation, particularly in pericytes, in supporting oligodendrogenesis and cognitive recovery after TBI. Understanding these mechanisms holds promise for the development of targeted therapies to address TBI-associated impairments.