Despite the increasing burden of mortality due to cardiovascular disease, the traditional risk factors fail to explain the complexity of the pathology of cardiovascular disease, especially in the context of chronic inflammation. Emerging scientific evidence indicates that dysbiosis of the oral, gut, and reproductive microbiome is associated with systemic vascular dysfunction. This review comprehensively discusses the available scientific data on the interactions between the mucosal colonizing microbiota and their modulation of whole-body inflammation and cardiovascular disease pathogenesis. It underlines the roles of microbial metabolites, including trimethylamine N-oxide and lipopolysaccharides, in immune activation, epithelial barrier cell injury, and their effects in endothelial activation, vascular remodeling and dysfunction, oxidative stress, and inflammation. This review describes the mechanistic interplay that drives atherosclerosis and vascular dysfunction, mediated by immune activation and cytokine-driven inflammatory cascades. Sex hormones influence the composition of the microbiota and the host immune responses, thereby influencing vascular disease manifestations and responses to therapy. These mechanisms present the potential of intervening at the microbial crossroads through microbiome-targeted approaches as an effective treatment strategy for cardiovascular disease.