Identifying disease-modifying therapies for Alzheimer’s disease (AD) has been an insurmountable challenge. To provide a new discovery tool for high-throughput compound screening, we used a simple yeast model that makes toxic amounts of β-amyloid (Aβ), a peptide central to AD pathology. Previous genetic analysis established that Aβ compromises yeast biology in a manner relevant to human AD. We screened 140,000 compounds for reversal of toxicity and identified a class of protective metal-binding compounds related to clioquinol (CQ), a compound that alleviates Aβ toxicity in mouse AD models. Treating yeast with CQ promoted rapid degradation of Aβ oligomers, rescuing cellular processes perturbed by this insidious peptide and restoring viability. Our approach provides a method for identifying compounds that may eventually help treat AD.