In diabetes, metabolic dysregulation, caused by hyperglycemia, leads to both structural and functional changes in cardiomyocytes and subsequently leads to the development of cardiomyopathy. Histone deacetylases (HDAC) are enzymes that regulate gene transcription. Their actions have been examined in the development of multiple disorders, such as cardiovascular diseases and diabetes. The use of HDAC inhibitors (HDACIs), as potential therapeutic agents against disease progression has yielded promising results. The present review article reports preclinical trials identified in which HDACIs were administered to mice suffering from diabetic cardiomyopathy (DCM), and discusses the role and mechanisms of action of HDAC and HDACIs in DCM. A review of the literature was performed using the PubMed database, aiming to identify publications in the English language concerning the role of HDACIs in DCM. More specifically, key words, separately and in various combinations, such as HDACIs, HDAC, diabetes, cardiomyopathy, heart failure and ischemia/reperfusion injury, were used. Furthermore, the references from all the articles were cross-checked in order to include any other eligible studies. The full-text articles assessed for eligibility were eight, covering the period from 2015 to 2019; finally, all of them were included. The use of HDACIs exhibited encouraging results against DCM progression through various mechanisms, including the reduction of reactive oxygen species generation, inflammatory cytokine production and fibrosis, and an increase in autophagy and angiogenesis.