Mitochondrial mutations cause bioenergetic defects associated with failures to use the electron transfer chain and oxidize substrates. These defects are exacerbated under energetic stress conditions and ultimately cause cell deterioration and death. However, little is known about cellular strategies that rescue mitochondrial stress failures and maintain cell survival under these conditions. Here, we have designed and performed a high-throughput chemical screen to identify small molecules that rescue human mitochondrial complex I mutations from energetic stress-induced cell death. The top positive hits were a series of sulfonylureas that efficiently maintain prolonged cell survival and growth under energetic stress conditions. The addition of galactose instead of glucose, to experimentally force mitochondrial respiration, triggered an initial ER stress response that was associated with IRE1α-dependent inflammatory signals including JNK and p38 MAP kinases in mutant cells. Sulfonylureas, similar to inhibition of IRE1α and p38 MAP kinase, potently blocked this ER stress inflammatory and cell death pathway and maintained viability and cell growth under severe energetic stress conditions. These studies reveal that sulfonylureas and specific inhibition of the IRE1α inflammatory pathway protect against cell death and can be used to rescue bioenergetic failures in mitochondrial complex I-mutated cells under stress conditions.