Arginase 2 (Arg2), an arginine-metabolizing, mitochondrial enzyme, has been recently found to be enriched in the striatum, and progressive loss of Arg2 has been proposed as a potential factor contributing to the pathogenesis of Huntington’s disease (HD), a disorder primarily involving this region of the brain. Although direct metabolic role of Arg2 is well established, the importance of this enzyme for striatal function and dysfunction is not known. The purpose of this work was to identify cellular pathways potentially controlled by Arg2 in the striatum. In our experiments, we have used wild-type C57Bl/6J mice and genetic mouse model of Arg2 loss (Arg2 KO mice; Arg2tm1Weo/J). By analyzing Arg2 levels in 19 different brain structures, we confirmed that striatum is one of the most Arg2-enriched regions in the brain. Immunohistochemical analyses showed that striatal Arg2 is present in medium spiny neurons (MSNs), the neuronal population specifically affected in the early stages of HD pathogenesis. Comparison of proteomes between WT and Arg2 KO mice indicated that Arg2 may support functioning of striatal mitochondria, as Arg2 deficiency resulted in alterations of selected components of respiratory chain and mitochondrial ribosomes. GO analysis confirmed enrichment of mitochondria-related terms, but also identified over-representation of mitochondrial proteins related to neurodegenerative diseases, including HD, among proteins altered in Arg2 KO striata. Summarizing, our results suggest that Arg2 supports the functioning of MSNs mitochondria, and loss of this enzyme may possibly contribute to HD pathogenesis through mitochondrial dysfunction.