Microglia are the innate immune cells of the central nervous system. They have many important physiological functions, from surveying the surrounding environment to synaptic pruning. However, following brain injury or during neurodegenerative diseases, microglia become 'activated,' migrate towards the site of injury, and produce inflammatory factors. Under neuropathological conditions, microglia may become excessively activated, a condition characterized by prolonged release of damaging proinflammatory factors. Mitochondrial function and dysfunction are increasingly being implicated in the process of microglial activation. This dissertation tested the overarching hypothesis that mitochondrial dysfunction stimulates proinflammatory microglial activation. Specifically, we found that in response to lipopolysaccharide (LPS) and interferon-γ (IFN-γ) in vitro, microglial mitochondria undergo structural remodeling and become significantly shortened. We utilized the putative mitochondrial fragmentation inhibitor mdivi-1 which successfully attenuated production of proinflammatory factors in vitro and in vivo. Surprisingly, mdivi-1 did not impair inflammation through modulation of mitochondrial structure, but instead impaired acetylation of the proinflammatory transcription factor NF-κB. We then set out to determine the importance of mitochondrial bioenergetic changes in microglial activation. We found that the combination of LPS/IFN-γ induced a significant impairment in mitochondrial oxygen consumption. This impairment was mediated by selective degradation of mitochondrial Complex I subunits at atmospheric 21% O2 and by nitric oxide at 3% O2, an oxygen tension thought to be more physiologically relevant to that present in the brain. Finally, we utilized the exogenous electron donor idebenone in an attempt to bypass this respiratory impairment. Indeed, we found that idebenone acutely reversed respiratory inhibition, and that this respiratory bypass was able to attenuate microglial production of proinflammatory factors. Together, the findings in this dissertation link mitochondrial structural and bioenergetic dysfunction to proinflammatory microglial activation, and move the field towards successfully finding a target for reversing damaging neuroinflammation following brain injury or in neurodegenerative disease.