Several physiopathological hypotheses have been studied to explain the link between heart failure (HF) and major depression (MD). An increase of monoamine oxidase (MAO) has recently been found as a factor involved in the development of HF. The aim of this review is to provide a complete overview of the involvement of MAOs in HF comorbidity of MD and to discuss the pharmacological options. Our work highlights the scientific evidence of MAO involvement in the development of HF. Studies focusing on MAO-A seem to have reproducible results on HF, establishing the effect of this enzyme as well as the protective effect of its inhibition. Fewer studies addressed MAO-B; results are nonetheless encouraging. Based on this knowledge, the hypothesis of a rise of MAO activity in HF seems to be well established. The large prevalence of comorbid MD in HF could be due to the deamination of monoamines linked with MAOs activity. In addition, MAOIs are effective in MD and well tolerated among the elderly according to the literature. This original hypothesis provides a new perspective in the use of MAOIs in HF patients with MD.