<p>Monoamine oxidase (MAO) helps regulate catecholaminergic signaling via metabolism of neurotransmitters epinephrine, norepinephrine, and dopamine—in turn producing the metabolites hydrogen peroxide (H₂O₂), ammonia (NH₄⁺), and corresponding catecholaldehydes. While MAO has been a key facet of neuroscience and mood disorder research for &gt; 60&#xa0;years, MAO-generated metabolites have been largely overlooked until recently when reports have begun to illustrate the reactivity of these metabolites and their pathogenic contributions to disease (e.g., inflammation, fibrosis, cell death). These findings have extended MAO’s biological relevance beyond the brain and, most notably, to the heart, where a large and growing body of literature clearly indicates a pathophysiologic role for MAO-mediated catecholamine metabolism in heart disease. Herein, we discuss the evidence connecting MAO to various cardiac injuries and disorders, as well as describe the known cardiotoxicity associated with MAO’s reactive metabolites, specifically in connection to cardiac pathophysiology. Potential therapeutic strategies for targeting MAO and its metabolites to prevent and treat heart disease are also discussed, and important knowledge gaps highlighted.</p> Graphical Abstract <p>Created using biorender.com</p> <p></p>