Ischemic heart disease and stroke are the most common causes of death world-wide. In both pathologies anoxia, the lack of oxygen, triggers profound metabolic and cellular changes. Sphingolipids have been implicated in anoxia injury, but the pathomechanism is unknown. Here we show that injury is caused by the accumulation of the non-canonical sphingolipid, 1-deoxydihydroceramide (DoxDHCer). We found that anoxia causes an imbalance between serine and alanine resulting in a switch from normal serine-derived sphinganine biosynthesis to non-canonical alanine-derived 1-deoxysphinganine. 1-deoxysphinganine is incorporated into DoxDHCer which impairs actin folding via the cytosolic chaperonin TRiC/CCT, leading to growth arrest in yeast and increased cell death upon ischemia-reperfusion injury in worms and mouse hearts. Prevention of DoxDHCer accumulation in worms and in mouse hearts resulted in decreased anoxia-induced injury. These findings unravel key metabolic changes during oxygen deprivation and point to novel strategies to avoid tissue damage and death.