<p>Atherosclerosis in postmenopausal women is a significant cardiovascular complication that is caused by estrogen deficiency, leading to increased inflammation and oxidative stress, and dysregulated lipid metabolism. The review summarizes the evidence gathered in ovariectomized mice models in order to determine mechanistic associations between different pharmacological therapeutic strategies and their impact on the progression of atherosclerosis in postmenopausal conditions. This review builds on an upstream hormonal signaling framework model of estrogen receptor-mediated pathways and the three main downstream mechanistic pillars: lipid handling, inflammatory and oxidative stress pathways, and endothelial homeostasis. In this framework context, downstream consequence mechanisms, including PCSK9 regulation and ferroptosis, are analyzed along with emerging evidence linking estrogen deficiency to modulation of the gut microbiota. The evidence shows the complex interconnections among hormonal, metabolic, and vascular processes underlying postmenopausal atherosclerosis, providing a translational framework for applying therapeutic interventions.</p> Graphical Abstract <p>Mechanistic framework of therapeutic strategies in post-menopausal atherosclerosis based on ovariectomized mouse models</p> <p></p>