Purpose: Ligustilide, an active ingredient from Rhizoma Chuanxiong, exhibits anti-inflammatory, antioxidant, and neuroprotective effects. We aim to evaluate the protective effects of ligustilide against cuprizone-induced sciatic nerve injury in rats by assessing autophagy, fibrosis and apoptosis. Methods: Cuprizone-induced sciatic nerve injury was investigated in rats. The severity of injury was evaluated using the open field test, the rotarod test, the wire grip test, and nerve conduction velocity measurements. Additionally, sections of the sciatic nerve were stained with Masson trichrome and immune-stained using an anti-mTOR antibody. Samples from the sciatic nerve were utilized to analyze gene expression and protein levels of mTOR, ATG5, beclin-1, TGF-ß, ß-catenin, and AMPK. The enzyme activities of caspases 3, 8, and 9 were assessed. Results: Ligustilide significantly improved performance in the open field test, extended grip endurance, and yielded enhanced results in the rotarod test among rats. Additionally, it increased nerve conduction velocity and restored the structural integrity of the sciatic nerves. Furthermore, ligustilide reduced the expression levels of mTOR, TGF-ß, ß-catenin, and AMPK, which are associated with the overexpression of ATG5 and beclin-1. Finally, ligustilide reduced the enzyme activities of caspases 3, 8, and 9. Conclusion: Ligustilide has demonstrated significant therapeutic effects in rat models of sciatic nerve injury. It enhances autophagy and inhibits fibrosis and apoptosis.  Kulcsszavak: AMP-activated protein kinase (AMPK), autophagy protein 5 (ATG5), beclin-1, ß-catenin, caspase-3/8/9, transforming growth factor-beta (TGF-ß), ligustilide, mechanistic target of rapamycin (mTOR)