Traumatic brain injury (TBI) is a leading cause of death in accidents, sports, and warfare. Additionally, TBI imposes a significant financial burden on individuals and governments, necessitating substantial financial support. It also severely diminishes the quality of life for patients and their caregivers. TBI is consisted of two distinct phases: the primary and secondary phases. The primary phase consists of numerous events that occur immediately after the injury or concussion but the second phase takes times and include several of responsive cascades that human body express against TBI. After TBI incidence, several cellular and molecular pathways (inflammatory, apoptotic, anti-oxidant) will be dysregulated. Over the years, numerous therapeutic approaches have been implemented to treat this debilitating condition, aiming to alleviate its symptoms and complications, while enhancing patients' quality of life. Consequently, the search for more efficient with less adverse effects therapeutic methods remains a priority. One herbal medication that has recently garnered considerable attention is saffron. Data were collected from Scopus, Google Scholar, PubMed, and Cochrane Library for clinical, in vivo and in vitro studies published in English between 1992 and Jan 2025. Search terms included "TBI" OR "Traumatic brain injury" AND "Saffron" AND "Safranal" AND "Crocin" AND "Crocetin" AND "Kaempferol". The initial search yielded approximately 3,000 manuscripts. After screening and full-text evaluation, as detailed in the search methodology, ten experiments (in-vitro & in-vivo) were ultimately included. Saffron showed to modulate various signaling pathways and cytokines such as NF-kB, NLRP3, Nrf2, HO-1, Bcl2, and Bax, which will lead to the improvement of TBI sign and symptoms and increase the quality of life. It has been demonstrated that this compound could play a multifactorial role in TBI treatment such as reduction in inflammation, apoptosis, and oxidative stress, while modulating microglia activation. The findings suggest that saffron may play a pivotal role in treating TBI and mitigating its complications by regulating various pathophysiological pathways. However, more clinical trials are necessary to evaluate saffron's effectiveness in individuals diagnosed with TBI. Clinical trials should focus on various areas such as saffrons' safety profile, adverse effects, the exact mechanism of action, its' impact on acute and chronic TBI, rehabilitation, and long-term neuroprotection.