Therapeutic interventions with proven efficacy in heart failure with reduced ejection fraction (HFrEF) have been unsuccessful in heart failure with preserved ejection fraction (HFpEF). The modifiable risk factor with the greatest impact on the development of HFpEF is hypertension. The objectives of this study were to establish a murine model of HFpEF associated with hypertension and to evaluate the effect of apo A-IMilano nanoparticles (MDCO-216) on established HFpEF in this model. Subcutaneous infusion of angiotensin II in combination with 1% NaCl in the drinking water was started at the age of 12 weeks in male C57BL/6 N mice and continued for the entire duration of the experiment. Treatment with MDCO-216 partially reversed established cardiac hypertrophy, cardiomyocyte hypertrophy, capillary rarefaction, and perivascular fibrosis in this model. Pressure-volume loop analysis was consistent with HFpEF in hypertension mice as evidenced by the preserved ejection fraction and a significant reduction of cardiac output (7.78 ± 0.56 ml/min versus 10.5 ± 0.7 ml/min; p < 0.01) and of the peak filling rate (p < 0.05). MDCO-216 completely reversed cardiac dysfunction and abolished heart failure as evidenced by the normal lung weight and normal biomarkers of heart failure. In conclusion, apo A-IMilano nanoparticles constitute an effective treatment for established hypertension-associated HFpEF.