Reduced oxidative demand or neuronal hypometabolism is a neuroprotective strategy used by several anoxia and hypoxia-tolerant species. The epaulette shark, Hemiscyllium ocellatum inhabits shallow reef platforms that can become hypoxic. Hypoxic pre-conditioning (eight cycles of 0.34 mg O2/l for 120 min, 12 h apart) was used to determine whether a reduction in oxidative metabolism could be elicited in the epaulette shark brain. Hypoxic pre-conditioning resulted in a significant overall reduction in oxidative activity in coronal sections of the brainstem, but key nuclei displayed heterogeneous levels of oxidative metabolism. Motor nuclei had significantly lower levels of oxidative activity while sensory nuclei did not. The epaulette shark's ability to enter this state of hypometabolism in response to hypoxic pre-conditioning revealed a neuroprotective mechanism, which would not only reduce neuronal damage during hypoxic exposure but also minimise re-oxygenation injury.