The innate immune response is thought to exert a dichotomous role in the brain. Indeed, although molecules of the innate immune response can promote repair mechanisms, during neuroinflammatory processes many harmful mediators are also released. Signs of neuroinflammation and neurodegeneration represent a ubiquitous pathological finding during the course of several different neurological diseases. Interestingly, it has been proposed that mitochondria may exert a crucial role in the pathogenesis of both inflammatory and neurodegenerative central nervous system disorders. In this review, we describe the mechanisms by which neuroinflammation and mitochondrial impairment may synergistically trigger a vicious cycle ultimately leading to neuronal death. In particular, we describe the close relationship existing among neuroinflammation, neurodegeneration, and mitochondrial impairment in three different widely-diffused neurological diseases in which these pathogenetic events coexist, namely multiple sclerosis, Parkinson's disease, and Alzheimer's disease.