Oxidative stress is associated with the progression of neurodegenerative diseases such as Parkinson’s disease (PD). In the present study, to examine whether a hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor has neuroprotective effect against α-synuclein (syn)-induced neurotoxicity in a cellular model, we used FG-4592, also known as roxadustat. To investigate the effect of FG-4592 against, we evaluated the α-syn protein level. mRNA levels of oxidative stress response genes whose transcription was regulated by HIF-1α were analyzed. Immunofluorescence staining with redox-sensitive dyes was also performed to examine the α-syn-induced oxidative stress. Previously, we succeeded in generating a new α-syn stably expressing cell line. In this cell line, we found that oxidative stress induced by α-syn caused cell death. FG-4592 exhibited significant neuroprotective effects against α-syn-related neurotoxicity. However, FG-4592 did not affect α-syn protein levels. FG-4592 induced heme oxygenase-1 (HO-1) expression levels in a concentration-dependent manner, suggesting that FG-4592 reduced oxidative stresses via the induction of HO-1. Thus, FG-4592 prevents α-syn-induced neurotoxicity through the reduction of oxidative stress by induction of HO-1.