Diabesotension, the coexistence of diabetes mellitus, obesity, and hypertension, represents an increasingly prevalent and clinically significant cardiometabolic syndrome. Epidemiological evidence highlights strong bidirectional relationships among these conditions, which together markedly elevate the risk of cardiovascular disease, stroke, nephropathy, and premature mortality. The pathophysiology of diabesotension is multifactorial, involving insulin resistance, chronic hyperglycemia, obesity-associated inflammation, endothelial dysfunction, sympathetic overactivity, and activation of the renin–angiotensin–aldosterone system (RAAS), culminating in adverse metabolic and hemodynamic interactions. Clinically, the synergistic presence of diabetes and hypertension accelerates both microvascular and macrovascular complications, leading to poorer outcomes than either condition alone. Recognizing diabesotension as a distinct clinical entity may facilitate more comprehensive care models and improved long-term outcomes, highlighting the need for continued research to refine risk stratification and optimize individualized treatment strategies. In this review, we focus on the genes implicated in key hallmarks of diabesotension, including insulin resistance, inflammation, RAAS activation, and oxidative stress, relevant clinical management strategies, and AI-based models for risk stratification of this triad of diseases.