This study investigates the role of histone deacetylase 6 (HDAC6) in heart failure with preserved ejection fraction (HFpEF) and its therapeutic potential. Using male HFpEF mouse models, the researchers found that inhibiting HDAC6 with TYA-018 effectively reversed established heart failure and its symptoms. In male mice lacking the *Hdac6* gene, HFpEF progression was delayed, and they were resistant to TYA-018's effects. The efficacy of TYA-018 was comparable to that of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination showed enhanced effects. Mechanistically, TYA-018 restored gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Additionally, TYA-018 inhibited the activation of human cardiac fibroblasts and enhanced mitochondrial respiratory capacity in cardiomyocytes. The findings suggest that HDAC6 impacts heart pathophysiology and is a promising target for HFpEF treatment. The study also developed a mouse model using a high-fat diet and moderate transverse aortic constriction to mimic the hemodynamic characteristics of HFpEF, which recapitulated key phenotypes of clinical HFpEF. The results support the direct role of HDAC6 in HFpEF pathophysiology and highlight the potential of HDAC6 inhibition as a therapeutic approach.This study investigates the role of histone deacetylase 6 (HDAC6) in heart failure with preserved ejection fraction (HFpEF) and its therapeutic potential. Using male HFpEF mouse models, the researchers found that inhibiting HDAC6 with TYA-018 effectively reversed established heart failure and its symptoms. In male mice lacking the *Hdac6* gene, HFpEF progression was delayed, and they were resistant to TYA-018's effects. The efficacy of TYA-018 was comparable to that of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination showed enhanced effects. Mechanistically, TYA-018 restored gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Additionally, TYA-018 inhibited the activation of human cardiac fibroblasts and enhanced mitochondrial respiratory capacity in cardiomyocytes. The findings suggest that HDAC6 impacts heart pathophysiology and is a promising target for HFpEF treatment. The study also developed a mouse model using a high-fat diet and moderate transverse aortic constriction to mimic the hemodynamic characteristics of HFpEF, which recapitulated key phenotypes of clinical HFpEF. The results support the direct role of HDAC6 in HFpEF pathophysiology and highlight the potential of HDAC6 inhibition as a therapeutic approach.