Chronic diseases—including diabetes mellitus, cardiovascular disease, chronic kidney disease, and autoimmune disorders—remain the leading causes of global morbidity and mortality. While biomedical pathophysiology defines the etiology and progression of these conditions, cultural factors significantly modulate how patients perceive illness, engage in treatment, and adhere to medical recommendations. This review synthesizes evidence from cross-cultural studies, with a specific focus on medical manifestations and therapeutic challenges, to examine how sociocultural determinants intersect with biological disease processes. We highlight nuanced case comparisons between South Asian, East Asian, Middle Eastern, African, Latinx, and Indigenous populations, illustrating how cultural constructs such as collectivism, fatalism, stigma, traditional medicine reliance, and health literacy directly influence outcomes in chronic disease management. Importantly, we integrate evidence-based recommendations for healthcare professionals, emphasizing culturally tailored interventions, precision medicine approaches, and the role of interdisciplinary care teams.