The lack of disease-modifying treatments for neurodegenerative disease stems in part from our rudimentary understanding of disease mechanisms and the paucity of targets for therapeutic intervention. Here we used an integrated discovery paradigm to identify a new therapeutic target for diseases caused by α-synuclein (α-syn), a small lipid-binding protein that misfolds and aggregates in Parkinson’s disease and other disorders. Using unbiased phenotypic screening, we identified a series of compounds that were cytoprotective against α-syn-mediated toxicity by inhibiting the highly conserved enzyme stearoyl-CoA desaturase (SCD). Critically, reducing the levels of unsaturated membrane lipids by inhibiting SCD reduced α-syn toxicity in human induced pluripotent stem cell (iPSC) neuronal models. Taken together, these findings suggest that inhibition of fatty acid desaturation has potential as a therapeutic approach for the treatment of Parkinson’s disease and other synucleinopathies. Display omitted •A series of oxadiazoles were identified that ameliorate α-synuclein toxicity in yeast•Oxadiazoles directly inhibit yeast (Ole1) and human (SCD) stearoyl-CoA desaturases•Inhibiting Ole1 restored α-synuclein localization and reversed trafficking defects•Inhibiting SCD protected human neurons from α-synuclein toxicity There are no treatments that target the underlying cause of synucleinopathies such as Parkinson’s disease. Using unbiased small-molecule phenotypic screening in yeast, Vincent et al. identify a potential therapeutic target, stearoyl-CoA desaturase (Ole1/SCD). Inhibiting SCD in human-derived neurons enhances their survival in the prescence of toxic α-synuclein.