Mitochondria are central to aerobic energy production and play a key role in neuronal signalling. During anoxia, however, the mitochondria of most vertebrates initiate deleterious cell death cascades. Nonetheless, a handful of vertebrate species, including some freshwater turtles, are remarkably tolerant of low oxygen environments and survive months of anoxia without apparent damage to brain tissue. This tolerance suggests that mitochondria in the brains of such species are adapted to withstand prolonged anoxia, but little is known about potential neuroprotective responses. In this study, we address such mechanisms by comparing mitochondrial function between brain tissues isolated from cold-acclimated red-eared slider turtles (Trachemys scripta elegans) exposed to two weeks of either normoxia or anoxia. We found that brain mitochondria from anoxia-acclimated turtles exhibited a unique phenotype of remodelling relative to normoxic controls, including: (i) decreased citrate synthase and F1FO-ATPase activity but maintained protein content, (ii) markedly reduced aerobic capacity, and (iii) mild uncoupling of the mitochondrial proton gradient. These data suggest that turtle brain mitochondria respond to low oxygen stress with a unique suite of changes tailored towards neuroprotection.