Background: Structural heart disease (SHD) encompasses a broad spectrum of valvular, septal, and congenital abnormalities affecting cardiac anatomy and function. The rapid evolution of transcatheter structural heart interventions has transformed the treatment paradigm, particularly among patients with multiple comorbidities who are deemed high-risk candidates for conventional surgery. Objective: To evaluate contemporary structural heart interventions in patients with multiple comorbid conditions and assess procedural success, clinical outcomes, peri-procedural complications, and long-term survival. Methods: A prospective observational cohort study involving 480 patients with structural heart disease and at least two significant comorbidities was conducted between January 2018 and December 2024. Patients underwent transcatheter aortic valve replacement (TAVR), transcatheter edge-to-edge mitral repair (TEER), left atrial appendage closure (LAAC), or transcatheter septal defect closure. Clinical, procedural, and follow-up data were analyzed. Results: Overall procedural success was achieved in 95.8% of cases. Despite a high burden of comorbidities including diabetes, chronic kidney disease, atrial fibrillation, chronic obstructive pulmonary disease, and frailty, structural interventions demonstrated significant improvements in symptoms, functional status, and quality of life. Thirty-day mortality was 2.9%, while one-year survival reached 88.7%. Conclusion: Structural heart interventions offer safe and effective treatment options for high-risk patients with multiple comorbidities. Careful patient selection, multidisciplinary heart-team evaluation, and advances in device technology contribute substantially to favorable outcomes.