Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics, to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and approaches that increase ketone concentrations exert beneficial effects in rodents and humans. However, the regulation of ketones in right ventricular failure (RVF) are unexplored. Here, we show in human pulmonary arterial hypertension (PAH), a compensatory ketosis is absent in patients with RVF. In the monocrotaline rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. These data suggest ketogenic therapies may particularly effective in RVF, and future studies evaluating the effects of ketones in RVF are warranted.