Several lines of evidence have suggested that mitochondrial dysfunction plays a key role in neurodegeneration. The mitochondrial function is a potential target for steroid hormones, which could exert protective activities in the brain and other tissues. The decrease of some sex steroids with aging has been associated with deleterious effects on brain function and progression to neurodegenerative diseases. Recent in vitro and in vivo evidence provides the basis for this review on the interplay of sex steroids and mitochondrial defects in preventing or improving pathological events in the central nervous system (CNS). In this article, the role of mitochondria under normal and pathological states will be discussed. In addition, we will review studies conducted on steroidal compounds, which have neuroprotective effects targeting mitochondria. It has been shown that these compounds could exert both direct and indirect effects on mitochondria that promote or preserve mitochondrial function under pathological circumstances, such as acute brain injury and chronic neurodegeneration.