Duchenne muscular dystrophy (DMD) is a progressive, X-linked disorder caused by the absence of dystrophin, leading to severe skeletal and cardiac muscle degeneration. This study evaluates the D2.mdx mouse model, a more severe model of DMD, to better understand the cardiac aspects of the disease and the impact of therapeutic interventions. We demonstrate that the D2.mdx mouse exhibits key features of DMD-related cardiomyopathy, including significant cardiac fibrosis, electrocardiogram abnormalities, diastolic dysfunction, and hypertension, mimicking the disease progression in humans. Importantly, we found that volitional wheel running improved cardiac function, alleviating left ventricular restriction and increasing survival age. Furthermore, when combined with micro-dystrophin gene therapy, exercise provided synergistic benefits, improving cardiac outcomes and delaying disease progression. This study underscores the utility of the D2.mdx model in preclinical DMD research and highlights the potential therapeutic role of exercise and gene therapy in mitigating cardiac dysfunction. These findings have significant implications for the design of clinical trials and therapeutic strategies for DMD, emphasizing the importance of addressing both skeletal and cardiac complications in future treatments.