<p>Deleterious perturbations in reactive oxygen species (ROS) and calcium (Ca²⁺) handling are key initiators of cell death in hypoxia-intolerant mammalian brain. Elevated cellular Ca²⁺ can also inhibit ROS scavengers, exacerbating the deleterious impact of hypoxia on redox homeostasis. Conversely, such perturbations are typically absent in the brain of hypoxia-tolerant animals, including naked mole-rats (NMRs; <i>Heterocephalus glaber</i>), in which a remarkable ability to scavenge ROS has been observed in cardiac and skeletal muscle. We asked if NMR brain possesses a similar ability to detoxify ROS and whether Ca²⁺ impairs ROS scavenging in NMR brain. To test these questions, we used the Amplex ultrared assay to measure the impact of Ca²⁺ on the ability of NMR brain homogenates to detoxify a bolus (50&#xa0;µl of 10&#xa0;µm H₂O₂) of exogenously applied H₂O₂ during different states of mitochondrial respiration. We report that (1) NMR brain mitochondria are net consumers of H₂O₂, (2) thioredoxin reductase is a major contributor to this scavenging capacity, and (3) Ca²⁺ inhibits ROS scavenging in all conditions tested. The rate of ROS consumption by NMR cortical homogenates is considerably greater than previously published measurements from rat and mouse brain and is less sensitive to inhibition by exogenous Ca²⁺, suggesting that NMRs have evolved an enhanced capacity to detoxify ROS. This ability is likely neuroprotective in this animal, which experiences regular bouts of intermittent hypoxia and reoxygenation of varying severity in its natural underground burrow habitat.</p>