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Desmin-related cardiomyopathy (DRC) is an inherited disorder characterized by progressive conduction abnormalities, arrhythmias, and heart failure. Although desmin aggregation is a defining pathological feature, the downstream signaling mechanisms driving disease progression remain poorly understood. In this study, whole-exome sequencing identified a heterozygous DES p.S13F variant in a multigenerational pedigree with a highly penetrant cardiac phenotype, and its pathogenic mechanisms were investigated using clinical data, zebrafish and mouse models, and cellular experiments. DES p.S13F expression induced desmin aggregation, cytoskeletal-associated protein abnormalities, mitochondrial dysfunction, oxidative stress, cardiomyocyte apoptosis, and adverse cardiac remodeling. Transcriptomic and protein analyses consistently revealed impaired canonical Notch signaling, with reduced NICD1 abundance in DES p.S13F-expressing mouse hearts and cardiomyocytes, providing a biochemical readout supporting impaired canonical NOTCH1 activation. Pharmacological Notch inhibition aggravated cardiac and cellular abnormalities, whereas Jagged1-mediated pathway activation ameliorated cardiac phenotypes in zebrafish and partially restored cytoskeletal-associated protein abundance while attenuating oxidative stress and apoptosis in DES p.S13F-expressing cardiomyocytes. Genetic NICD1 overexpression produced concordant protective effects, further supporting the functional involvement of canonical Notch signaling. Collectively, these findings identify Notch signaling insufficiency as a functionally relevant disease-modifying mechanism in DES p.S13F-associated cardiomyopathy and suggest that restoration of canonical Notch signaling may represent a potential therapeutic strategy for desmin-related cardiomyopathy.