Background: Parkinson’s disease is mainly specified by progressive and selective death of dopaminergic neurons. Crocus sativusL. (saffron) has been widely used to cure a diverse range of diseases in herbal medicine. Aim: The aim of the present study is to investigate the neuroprotective effects of saffron on arsenic-induced neurotoxicity, which was performed in human neuroblastoma SH-SY5Y cell line as an in vitro model of Parkinson’s disease and to confirm whether the neuroprotective effects of saffron on Parkinson’s disease are mainly due to their interactions with antioxidant systems. Moreover, as the antioxidant effect of N-acetylcysteine and its effectiveness as an antioxidant agent are proven, we compared saffron with NAC to control saffron extract. Materials and Methods: The induction of cell damage was done by arsenic and the survival of the cells was measured using the MTT assay. In addition, the assessment of the generation of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential was done using fluorescence spectrophotometry method. Furthermore, immunoblotting analysis was performed to precisely determine the biomarkers level for apoptosis in the cells. Results: Our study indicated that arsenic had the ability to decrease cells survival rate, enhance the loss of mitochondrial membrane potential and increase the levels of intracellular ROS, c-Fos ratio and caspease-3. Pretreatment of cells with NAC (5 mM) and saffron aqueous extract (10mg/ml) significantly attenuated the mentioned effects in arsenic-treated cells. Conclusion: The outcome of the study has shown that the protective effects of NAC and saffron aqueous extract are produced by their antioxidant and anti-apoptotic properties and their therapeutic potential is demonstrated in the treatment of Parkinson’s disease.