Objective <p>Spinal cord injury (SCI) is characterized by its high incidence, high disability rate, and high treatment costs, making the development of effective therapeutic strategies a major focus. Secondary injury mechanisms in SCI involve complex processes such as inflammation, oxidative stress, and apoptosis, which are critical to patient prognosis.</p> Methods <p>This study investigates the role of SIRT1 in SCI repair, particularly its molecular mechanisms in regulating the P53/Nrf2 signaling pathway. By constructing a recombinant adenovirus overexpressing SIRT1 and conducting both in vitro and in vivo validation, we found that SIRT1 modulates the P53/Nrf2 pathway by downregulating P53 and upregulating Nrf2 expression, significantly inhibiting the expression of inflammatory factors TNF-α, IL-1β, and IL-6, while increasing the expression of the anti-inflammatory factor IL-10. Additionally, SIRT1 reduced apoptosis by regulating Bax and Bcl-2 expression, and enhanced cellular antioxidant capacity through activation of Nrf2. These regulatory effects significantly promoted motor function recovery in SCI rats.</p> Conclusion <p>This study provides mechanistic evidence for the neuroprotective role of SIRT1 in SCI and establishes a foundation for considering SIRT1 as a novel therapeutic target for SCI.</p>