Clinical trials demonstrate baroreflex activation therapy (BAT) reduces LV mass and blood pressure (BP) in hypertensive patients and in patients with hypertensive heart failure with preserved ejection fraction (HFpEF). It is thought that high sympathetic nerve activity (SNA) in the heart plays a role in the disease progression seen in these patients. However, the impact of BAT on hemodynamics, cardiac SNA, and disease progression during HFpEF is unknown. In the present study, we used HumMod, a large physiology model to predict the time-dependent changes of BAT during HFpEF. Our results demonstrate a progressive cardiac hypertrophy and fibrosis during HFpEF. After 6 months of BAT however, left ventricular mass was reduced (-11%), associated with decreased blood pressure, decreased cardiac SNA, and restoration of β1-adrenergic activity. Interestingly, when cardiac SNA suppression was blocked during BAT, the improvement in cardiac mass was attenuated. These simulations indicate that the suppression of cardiac SNA could be the primary determinant of the cardioprotective effects from BAT in this HF population.