Abstract Background Vanishing white matter disease (VWMD) is a rare disease caused by mutations of the guanine exchange factor eIF2B. VWMD typically presents with juvenile onset, and there are few treatments for the disease. Recent progress in the field has established mitochondrial dysfunction and endoplasmic reticulum (ER) stress to be strongly implicated in observed glial cell pathology. Drug repurposing offers a rapid approach toward translation of therapeutics using already-licensed drugs. Objective The aim of this study was to use fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes from patients bearing the EIF2B5^R113H/A403V or EIF2B2^G200V/E213G VWMD mutations to identify potential repurposable FDA-approved drugs based on in vitro assays. Methods Cell viability in the presence or absence of stress was assessed by resazurin reduction activity and assays for mitochondrial membrane potential and oxidative stress by tetramethylrhodamine and dichlorofluorescein-based assays, respectively. Integrated stress response markers, including eIF2α phosphorylation, GADD34 and CHOP were quantified by fluorescent western blot. Results Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under induced stress conditions. A drug screen from a 2400 FDA-approved drug library with EIF2B5^R113H/A403V VWMD patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of candidate drugs, including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2–73, and preclinical ISRIB, increased cell survival of EIF2B5^R113H/A403V or EIF2B2^G200V/E213G VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. Ursodiol demonstrated capacity to ameliorate oxidative stress and loss of mitochondrial membrane potential in VWMD patient iPSC-derived astrocytes in the presence or absence of stress conditions. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo.