<p>Peripheral nerve injury (PNI) is a common condition that leads to the partial loss of function in the sensory, motor, and autonomic nervous systems. The peripheral nervous system has an inherent capacity to regenerate after injury and re-innervate its target organs, but full functional recovery is rare. In recent years, there has been growing interest in identifying drugs that can promote axonal regeneration and outgrowth following PNI. Epothilone B (EpoB) is an FDA-approved antineoplastic agent that promotes tubulin polymerization and enhances the stability of microtubules. Recently, the regenerative effects of EpoB in the central nervous system have garnered attention, but its potential therapeutic effects on peripheral nerve regeneration remain underexplored. This study utilized a sciatic nerve transection and anastomosis model in rats to evaluate the effects of EpoB on neuroprotein expression following nerve injury. Behavioral analysis, Masson’s trichrome staining, and immunofluorescence staining were conducted to assess the impact of EpoB on sciatic nerve regeneration. Over time, motor recovery and muscle reinnervation were observed, with Sciatic Functional Index (SFI) scores higher in the EpoB-treated group compared to the vehicle group. The expression of fibronectin (FN) was significantly lower in the EpoB group, while the expression of Tau, neurofilament-M (NF-M), and growth-associated protein-43 (GAP-43) was significantly higher. In conclusion, EpoB treatment significantly increases the expression of Tau, NF-M, and GAP-43, suggesting a positive effect on axonal regeneration and repair.</p>