TY1, a synthetic non-coding RNA (ncRNA) bioinspired by small Y RNAs abundant in extracellular vesicles (EVs), decreases cGAS/STING activation in myocardial infarction and thereby attenuates inflammation. Motivated by the concept that heart failure with preserved ejection fraction (HFpEF) is a systemic inflammatory disease, we tested TY1 in a murine model of HFpEF. Intravenous TY1, packaged in a transfection reagent, reversed the cardiac and systemic manifestations of HFpEF in two-hit obese-hypertensive mice, without inducing weight loss. The effects of TY1 were specific, insofar as they were not reproduced by a control RNA of the same nucleotide content but in scrambled order. TY1 consistently suppressed myocardial stress-induced MAP kinase signaling, as well as downstream inflammatory, fibrotic, and hypertrophic gene pathways in heart tissue. TY1 not only prevented but actually reversed key pathological processes underlying HFpEF, with no evidence of toxicity. Most noteworthy from a practical perspective, the effects of intravenous TY1 were reproduced by feeding HFpEF mice an oral micellar formulation of TY1. As the prototype for a novel class of ncRNA drugs which target cell stress, TY1 exhibits exceptional disease-modifying bioactivity in HFpEF.