The objective of this study was to compare the neurotoxic effect of Endosequence BC sealer and MTA FilLapex sealer versus AH-plus by assessing the nerve conduction velocity(NCV) of isolated rat sciatic nerve and features of histopathological neurotoxic effect. Methods: fifty seven white female albino rats were used in this study and grouped into three equal groups, 19 rats for each sealer group. All sealers were prepared according to manufacturer's instruction and applied on the all entire length of the isolated rat sciatic nerve. The neurotoxicity of the root canal sealers(RCSs) was assessed by calculating the (NCV) of isolated rat sciatic nerve before ,after 5 mins and after 30 mins of sealer application on the nerve by the electrophysiologic data acquisition system (power lab) device. NCV can determine the nerve destruction and damage. Sciatic nerve samples that revealed a significant decrease in NCV due to severe neurotoxic effects had been selected for subsequent histopathological analysis. Results: The only statistical significant difference of the NCVs between groups was observed after 30 mins between AH-Plus and Endosequence and between AH-Plus and MTA Fillapex so AH-Plus has the most neurotoxic effects followed by MTA Fillapex and the least one was Endosequence bc Histological examination of haematoxylin and eosin (H&E) stained sections of sciatic nerves with a significant decrease in NCV revealed that there were marked histopathological changes for AH-plus group compared to Endosequence bc and MTA Fillapex groups. Due to the very limited research papers on the neurotoxicity of the endodontic materials we conducted our study. Conclusion: Overextension with pushing of resin based cement into periapical tissue should be avoided otherwise a paraesthesia might occurs moreover, measuring the NCV was proved to be a valuable tool in assessing the neurotoxic effect of the root canal sealer and Histopathological data are essential tool to confirm the electrophysiological findings.