Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion of CAG repeats in the HD gene encoding for huntingtin (Htt), resulting in progressive death of striatal neurons, with clinical symptoms of chorea, dementia and dramatic weight loss. Metabolic and mitochondrial dysfunction caused by the expanded polyglutamine sequence have been described along with other mechanisms of neurodegeneration previously described in human tissues and animal models of HD. In this review, we focus on mitochondrial and metabolic disturbances affecting both the central nervous system and peripheral cells, including mitochondrial DNA damage, mitochondrial complexes defects, loss of calcium homeostasis and transcriptional deregulation. Glucose abnormalities have also been described in peripheral tissues of HD patients and in HD animal and cellular models. Moreover, there are no effective neuroprotective treatments available in HD. Thus, we briefly discuss the role of creatine and coenzyme Q10 that target mitochondrial dysfunction and impaired bioenergetics and have been previously used in HD clinical trials.