The most common cause of mortality in Duchenne muscular dystrophy (DMD) is cardiopulmonary failure. Various clinical and commercial gene therapies aim to alter DMD disease trajectory with adeno-associated virus- (AAV) mediated delivery of expression constructs for microdystrophins (µDys), truncated dystrophin proteins that retain key functional elements of the full-length protein. We recently showed that the dystrophin C-Terminal (CT) domain enhances the effectiveness of a µDys construct in skeletal muscle. However, the impact of the dystrophin CT domain on cardiac health and function remains unknown. Although dystrophin-deficient mdx mice do not fully phenocopy human DMD, repeated isoproterenol injections induce a dilated cardiac phenotype that resembles DMD-associated cardiomyopathy. We compared µDys constructs with or without the CT domain (termed µDysCT194 and µDysCT48, respectively) for their abilities to resist pharmacologically induced cardiac damage in mdx mice. Both µDysCT194 and µDysCT48 were packaged into AAVhu32 and administered intravenously at a dose of 2×1013 GC/kg. 4 weeks after AAV.µDys administration, we performed daily isoproterenol injections for 10 consecutive days and assessed cardiac function and remodeling through echocardiography and histology. Cardiac damage, as measured by serum cardiac troponin, was increased in mdx hearts after the first injection and prevented by µDys (39.7 ng/ml, mdx Vehicle vs. 0.7, C57Bl/10, 2.9, µDysCT194, and 9.7, µDysCT48). Repeated isoproterenol administration dilated mdx left ventricles (LVEDd 4.3mm vs. 3.9mm, C57Bl/10), induced fibrosis (35.2% vs. 18.9%, C57Bl/10), reduced fractional shortening (0.24 vs. 0.33, C57Bl/10) and reduced ejection fraction (43.0% vs. 54.4% in C57Bl/10). Both µDys provided ameliorated these effects, with µDysCT194 providing a stronger rescue on LVEDd (3.9mm, µDysCT194 vs. 4.1mm, µDysCT48), fibrosis (9.8%, µDysCT194 vs. 16.4%, µDysCT48), fractional shortening (0.33, µDysCT194 vs. 0.29, µDysCT48), and ejection fraction (54.6%, µDysCT194 vs. 49.4%, µDysCT48). These results provide evidence that the dystrophin CT domain may enhance protection against pathological remodeling in dystrophin-deficient hearts.