Background Mitochondrial dysfunction, characterized by abnormalities of mitochondrial biogenesis, dynamics, trafficking, and alterations in the synthesis of high-energy molecules, seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington’s disease (HD). Meldonium is a small molecule that inhibits endogenous carnitine synthesis and carnitine cell uptake. The decrease of carnitine availability inside the cell induces a significant reprogramming of cell metabolic pathways that apparently counters the mitochondrial dysfunction, at least in the case of heart or brain ischemia. Aims To evaluate neuroprotective actions of meldonium in both in vitro and in vivo HD models. Methods We used STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein (mHtt), and a transgenic Drosophila model of HD in which the expression of Htt, with a 128Q expansion (Q128HD-FL) in the nervous system, led to progressive motor performance deficits. Results We found that meldonium could prevent cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells. Meldonium could also reduce the accumulation of mHtt aggregates inside the cell. In addition, meldonium was able to upregulate the expression of PGC-1α, which is a master co-regulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, as well as a potential HD target. As expected, the increase of PGC-1α was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Interestingly, when given per os, meldonium significantly alleviated motor dysfunction and prolonged the survival of transgenic Drosophila model of HD. Conclusions Our study strongly suggests, after considering these factors together, that meldonium (itself or as a lead structure for the synthesis of novel drugs) is a potential treatment for the management of HD.