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Objective: Decompression surgery in patients with spinal cord injury (SCI) has a neuroprotective effect by alleviating secondary injury and improving neurological outcomes. N-Acetylcysteine (NAC), a drug approved by the United States Food and Drug Administration, has been shown to play neuroprotective roles via attenuation of apoptosis and inflammation. The purpose of the present study was to investigate the effects of early or late decompression surgery in combination with NAC administration on acute SCI, as well as investigate the underlying mechanisms of its actions., Methods: In this study, an acute SCI model was established in rats. The rats were treated with decompression surgery 24/48 h post-SCI in combination with or without NAC., Results: The results showed that decompression surgery in combination with NAC lead to a better outcome than decompression alone, as demonstrated by the higher Basso, Beattie, and Bresnahan scores. Histopathological examination demonstrated that early decompression surgery in combination with NAC exerted the best therapeutic effect on spinal cord recovery, which was further confirmed by the extent of inflammation and apoptosis. Additionally, we found that NAC might compensate for a lack of late surgery., Conclusions: Collectively, early decompression surgery and NAC could be a promising combination for the treatment of acute SCI, and its therapeutic effects may be associated with the regulation of inflammation and apoptosis.