Technical Abstract: Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal muscle insulin resistance. We tested the hypothesis that "western" and high-fat diets differentially cause maladaptation of cardiac and skeletal muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed low-fat, "western," or high-fat (10%, 45%, or 60% calories from fat, respectively) diet for acute (1 day to 1 week), short (4 to 8 weeks), intermediate (16 to 24 weeks), or long (32 to 48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high-fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with western diet in the acute, short, and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either western or high-fat feeding. Fatty acid-responsive genes, including pyruvate dehydrogenase kinase 4 and cytosolic thioesterase 1, increased in heart and soleus muscle to a greater extent with feeding a high-fat diet, versus a western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with western diet.