An estimated 13.9% of Americans currently meet criteria for an alcohol use disorder. Ultimately, chronic alcohol use may result in neurological deficits, with up to 85% of alcoholics exhibiting signs of cognitive decline. However, biochemical and behavioral factors contributing to this decline have remained elusive. Our ongoing research program encompasses a multi-tiered screening of a natural product library and validation process to provide novel information about mechanisms underlying these deficits and to identify novel chemical scaffolds to be exploited in the development of pharmacological treatments for alcohol use disorders in a rodent organotypic hippocampal slice culture mode. Experiment 1 sought to establish a 48 h high throughput model for testing novel scaffolds against ethanol (EtOH) toxicity. Experiment 2 tested multiple natural product compounds for their ability to attenuate ethanol-induced cytotoxicity. Results from Experiment 1 revealed EtOH (100 mM) induced significant cytotoxicity at 48 h. Trolox (100 µM), a potent antioxidant, was found to reduce ethanol-induced cytotoxicity in this assay. Experiment 2 revealed two spoxazomicins (1, 1-1) demonstrated potent cytoprotective effects against ethanol toxicity. These findings highlight the potential applications of these novel scaffolds for use in the treatment of alcohol use disorder.