Objective(s): Resveratrol has been recognized as a potential therapeutic drug in spinal cord injury (SCI). Sirtuin 1 (SIRT1) is vital in the regulation of apoptosis and cell stress response. In this research, our purpose was to explore the mechanisms of resveratrol on neuroprotection and to explore the role of SIRT1. Materials and Methods: We used lipopolysaccharide (LPS) in the VSC4. 1 spinal cord neuron cell line to mimic the micro-environment of the injured spinal cord. The apoptosis of VSC4. 1 motoneurons was assessed by TUNEL staining, Western blot, and RT-PCR. Immunofluorescence staining was used to observe the expression site of SIRT1, LC3-B, and Beclin-1, and their protein levels were measured by Western blot and RT-PCR. Results: Our results showed that resveratrol inhibits LPS-induced apoptosis in VSC4. 1 motoneurons. Levels of LC3-B, beclin-1, and SIRT1 indicated a significant increase after resveratrol treatment. But, if autophagy was inhibited, apoptosis in VSC4. 1 motoneurons significantly increased. When the cells were treated with EX527, a SIRT1 inhibitor, the protein contents of LC3-B and Beclin-1 were suppressed. Conclusion: Resveratrol inhibits apoptosis through promoting autophagy in VSC4. 1 motoneurons. SIRT1 was involved in autophagy activated by resveratrol in VSC4. 1 motoneurons.