Every day clinicians prescribe Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and above all sodium-glucose transporter 2 inhibitors (SGLT2i) as cardioprotective agents. Probably oxidative stress induced by high glucose is a common target of SGLT2i and GLP-1RAs, but the cellular mechanisms modulated by these drugs have not been completely delineated as well as the differences with “old” glucose-lowering agents. Thus, we designed this study to investigate the different action of SGLT2i-empagliflozin (E), GLP-1RA-semaglutide (S) and metformin (M) on cardiac damage induced by hyperglycaemia. To perform our experiments we used H9c2 cells, a ventricular cardiomyoblasts cell line, characterized by a fusiform shape, a mononucleated state. Mitochondrial reactive oxygen species (ROS); dramatically risen in HG cells, E as well as S counteracted HG-induced damages whereas M action is inadequate (MitoSOXTM). Similarly, in HG cells the expression of mitochondrial encoded cytochrome c oxidase I (MTCO1) was downregulated and above all E and S treatment restored it. Abnormal ROS production is linked to structural alterations and ERK activation. All treatments but above all E and S downregulated ERK activation. H9c2 cells grown in hyperglycaemic medium acquired a hypertrophic and rounded morphology shape: E and S restore e both cellular shape and size, whereas M only inhibited hypertrophic rearrangements (phalloidin staning). Finally, chronic high glucose inhibits AMPK and AKT activation and respectively E and S enhance the phosphorylation of these kinases. M action was restricted and similar to E. This study suggests that E and S alleviate hyperglycaemia-induced injury in cardiac cells acting on different cellular pathway and provides new therapeutic insights into E and S as a cardioprotective agent.