One half of adults have hypertension, which is a major risk factor for stroke, myocardial infarction, heart failure, and vascular dementia. There is an urgent need for new therapies, particularly for women with hypertension. Hypertension affects women in all phases of life; however, the hypertension rate increases in women much more steeply, and hypertensive vascular and kidney damage is significantly higher in women. Despite great burden, only 1 in 4 patients have their blood pressure under control. Hypertension accounts for 1 in 5 deaths among American women, posing a greater burden for women than men. Meanwhile, female-specific aspects of hypertension are poorly understood, and women or female-specific risk factors are understudied in basic, clinical, and population research and hypertension guidelines. Understanding these mechanisms can help to develop new therapies. Endothelial dysfunction has a profound prognostic implication predicting adverse cardiovascular events. We suggest that female antihypertensive protection is critically dependent on mitochondrial pathways preserving endothelial function. Metabolic disorders and oxidative stress contribute to the pathogenesis of these conditions, which are linked to mitochondrial dysfunction. Proteomic studies showed higher expression of mitochondrial fatty acid oxidation and antioxidant enzymes in females, and oxidative damage is lower in females compared with males. Meanwhile, the actual activity of these mitochondrial metabolic and antioxidant enzymes is regulated by acetylation, but sex-specific differences in mitochondrial acetylation in vascular disease have not been studied. In the present review, we will discuss potential sex differences in mitochondrial protein acetylation and its implications in metabolic conditions, oxidative stress, vascular dysfunction, hypertension, and cardiovascular disease.