Cardiovascular diseases are leading causes of death globally, often manifesting after years of atherosclerosis (AS) progression. In this study, we investigated the atheroprotective effects of three different sources of glucomannan, Dendrobium officinale polysaccharide, Konjac glucomannan, and Aloe vera polysaccharide (AVP), using an in vitro ox-LDL-induced foam cell model and an in vivo high-fat high-cholesterol diet-fed ApoE^−/− mouse model. Both settings indicate that AVP exerts the most significant atheroprotective effects. It inhibits lipid absorption and enhances the regulation of lipid homeostasis by the liver X receptor, thereby suppressing the formation of foam cells. It can also alleviate ox-LDL-induced oxidative stress and apoptosis in RAW 264.7 cells. Animal experiments show that AVP can prevent the formation of atherosclerotic plaques and coronary artery fibrosis, while also reducing circulating IL-1β levels. Furthermore, liver transcriptomic analysis shows that AVP inhibits inflammation and promotes bile acid excretion and transport by upregulating the farnesoid X receptor. Additionally, metagenomic analysis indicates that AVP can significantly reverse the microbial alterations associated with AS. Specific gut microbes, such as Prevotella, may partially mediate the effects of AVP through the gut–liver axis. This is the first study to report the atheroprotective effects of AVP, demonstrating that it alleviates atherosclerosis by restoring lipid metabolism homeostasis and modulating the gut microbiome.