The global burden of cardiometabolic pathologies is expected to increase in the near future with most of related cardiovascular deaths occurring in low and middle-income countries. The major pathomechanisms that underlie these pathologies are chronic oxidative stress and low-grade inflammation, which promote each other in a vicious circle leading to both disease progression and the occurrence of complications. Heart failure, the end-stage of cardiometabolic diseases, is regarded as a ”systemic mitochondrial cytopathy” since mitochondria are the major sites of reactive oxygen species (ROS) generation. Monoamine oxidase (MAO) with two isoforms, MAO-A and MAO-B, located at the outer mitochondrial membrane, has emerged in the recent years as a constant enzymatic source of deleterious ROS in the diseased cardiovascular system whose expression and/or activity is increasing with the age. Moreover, inflammation is responsible for age-independent increase in MAO expression. A large body of research demonstrated the role of antidiabetics in improving the outcome of non-diabetic and diabetic patients with cardiovascular diseases yet the underlying pathomechanisms remain elusive. Metformin, the central pillar of therapy in type 2 diabetes, is the ”good old drug” with incompletely understood pleiotropic effects, including the antioxidant, which are responsible for the cardiovascular protection and anti-ageing properties. The sodium-glucose-cotransporter 2 inhibitors (SGLT-2i) are novel antidiabetic drugs which exert cardiovascular protection in the absence of diabetes via partially elucidated off-target effects. Here we provide evidence that MAO is a novel target of both classic and new antidiabetics in the human cardiovascular system.