Elevated red blood cell distribution width (RDW) has been found to be associated with the occurrence of ischemic stroke. However, there is no defined relationship between RDW and neuronal damage in acute ischemic stroke (AIS). This study was designed to determine the relationship between RDW and neuronal damage in AIS patients. A total of 442 consecutive AIS patients from January 2018 to June 2019 were evaluated for neuronal damage, which was estimated by serum neuron-specific enolase (NSE) levels. Red blood cell distribution width-standard deviation (RDW-SD), a parameter that reflects the heterogeneity of red blood cell volume, was also assessed. We evaluated the association between the RDW-SD and serum NSE level through multivariate-adjusted linear regression analysis. Both the serum NSE level and the incidence of high NSE increased according to the increased RDW-SD tertile in AIS patients (p<0.01). There was a positive correlation between RDW-SD and serum NSE levels (r=0.275, 95% CI: 0.187-0.359, p<0.001). The beta coefficients (95% CI) between RDW-SD and serum NSE levels were 0.32 (0.21-0.42, p<0.001) and 0.26 (0.15-0.38, p<0.001), respectively, in AIS patients before and after adjusting for potential confounders. In conclusion, we found a significant positive association between RDW-SD and neuronal damage in AIS patients.