Spinal cord injury (SCI) is a highly disabling trauma of the central nervous system, characterized by a complex pathological process involving intertwined multiple mechanisms. Key pathological events include excessive activation of neuroinflammation, oxidative stress injury, neuronal apoptosis, autophagic dysfunction, and energy metabolism imbalance, which severely disrupt the integrity of spinal cord neural function and significantly reduce patients’ quality of life. Currently, clinical neurorepair strategies for SCI have limited efficacy and are difficult to achieve synergistic intervention targeting multiple pathological links. Therefore, exploring novel core therapeutic targets and precise intervention regimens has become an urgent need in this field. The Sirtuins family (SIRT1-SIRT7), as NAD⁺-dependent deacetylases, play a central role in critical biological processes such as cellular metabolism regulation, immune homeostasis maintenance, and stress injury repair, and have been identified as potential intervention targets for neurological diseases. This review systematically summarizes the cellular localization and core biological functions of each member of the Sirtuins family, with a focus on their regulatory roles and molecular mechanisms in the pathological process of SCI: SIRT1, 3, 5, and 6 inhibit the excessive activation of the NF-κB pathway and block NLRP3 inflammasome assembly through deacetylation modification, thereby participating in the regulation of neuroinflammation after SCI; meanwhile, they alleviate oxidative stress injury in spinal cord tissues by activating the Nrf2 antioxidant pathway and enhancing the activity of antioxidant enzymes such as SOD and NADPH, forming a “anti-inflammatory-antioxidant” synergistic protective effect. SIRT7 delays neuronal apoptosis by promoting DNA damage repair and inhibiting apoptotic signaling pathways. SIRT3 and SIRT5 target mitochondrial function, improve mitochondrial energy metabolism by regulating the modification status of enzymes involved in the tricarboxylic acid cycle and oxidative phosphorylation, and restore autophagic homeostasis by modulating the acetylation levels of FOXO3a and AMPK, providing metabolic support for neural repair. We summarize that a variety of natural Chinese herbal components (e.g., resveratrol, matrine) and synthetic compounds (e.g., SRT1720, AGK2) can influence the pathological progression of SCI by targeting and regulating members of the Sirtuins family. We propose that Sirtuins-targeted combined therapeutic strategies (e.g., combined with stem cell transplantation, neurotrophic factor supplementation, or antioxidant intervention) are expected to break through the limitations of single therapies and enhance the repair effect of SCI through multi-mechanism synergistic actions. In conclusion, the Sirtuins family exhibits critical mechanisms of action and potential intervention value in the pathophysiological process of SCI. This review summarizes and prospects novel Sirtuins-targeted therapeutic strategies, aiming to provide new insights for basic research and clinical translation in this field.