The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPARα) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPARα operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPARα-mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPARα and provides fundamental insights into the molecular regulation of cardiac lipid metabolism.