Background Mutations in ATP1A2 gene encoding the Na,K‐ATPase α ₂ isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K‐ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2–associated G301R mutation in the Atp1a2 gene (α ₂ ^+/G301R mice) and matching wild‐type controls were compared. Reduced expression of the Na,K‐ATPase α ₂ isoform and increased expression of the α ₁ isoform were observed in hearts from α ₂ ^+/G301R mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8‐month‐old α ₂ ^+/G301R mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3‐month‐old α ₂ ^+/G301R mice were similar to wild‐type mice. Amplified Na,K‐ATPase–dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen‐activated protein kinase) signaling was observed in hearts from 8‐month‐old α ₂ ^+/G301R mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure–associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´‐tetrachloro‐1,1´,3,3´‐tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8‐month‐old α ₂ ^+/G301R mice. Conclusions Our findings suggest that ATP1A2 mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K‐ATPase–dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.