Endoplasmic reticulum (ER) stress plays a key role in the development of neurodegenerative diseases, including Parkinson's disease (PD). Sulforaphane (SF) is a natural drug derived from isothiocyanate found in cruciferous vegetables. Although there are reports indicating that SF is a potential candidate for PD treatment, there have been no reports on the effects of SF on ER stress in PD. In this study, we investigated the cytoprotective effects of SF on 6-hydroxydopamine (6-OHDA)-induced ER stress in rat PC12 cells. Pre-treatment with SF elicited cytoprotection against 6-OHDA-induced cytotoxicity. Consistent with its cytoprotective action, SF significantly inhibited subsequent ER stress, including the expression of Bip and the C/EBP homologous protein. We also found that transfection with NF-E2-related factor-2 (Nrf2) siRNA reversed the inhibitory effects of SF on 6-OHDA-induced ER stress responses. In conclusion, our results show that SF can prevent ER stress response induced by 6-OHDA through the activation of Nrf2. SF may be a therapeutic candidate for the treatment of ER stress-associated neural diseases, including PD.