Dipeptidyl aminopeptidase-like protein 6 (DPP6) is a subunit of the K_v4 channels that carry the transient-outward current (I_to) in cardiac Purkinje cells (PCs) and ventricular myocytes (VMs). DPP6 genetic variants have been linked to severe arrhythmia syndromes. Given the influence of other I_to subunits on the Na_v1.5-mediated cardiac sodium current (I_Na), we examined whether DPP6 regulates both I_to and I_Na. We explored the impact of the DPP6 missense variants c.821G>A and c.637C>T, segregating in families with long-QT syndrome (LQTS), and c.2252C>T and c.1578G>C, associated with J-wave syndromes (JWSs) and unexplained syncope. In human and mouse heart slices, DPP6 localized within 40 nanometers of Na_v1.5. Functionally, DPP6 reduced I_Na and increased I_to density in transfected Chinese hamster ovary cells. DPP6 variants linked to LQTS and JWSs led to a hypo- and hyperinhibition of I_Na, respectively. Conversely, I_to was increased by the JWS variants and decreased by the LQTS variants coexpressed with PC (but not VM) I_to subunits. These findings were validated in human induced pluripotent stem cell-derived cardiomyocytes. In silico modeling of I_Na and I_to data into PC and VM single-cell action potentials, subsequently integrated in two-dimensional tissue simulations, produced steep repolarization gradients for LQTS-c.821G>A versus slowed conduction for JWS-c.2252C>T. Noninvasive electrocardiographic imaging, used for advanced clinical phenotyping, showed dispersed and prolonged repolarization in the DPP6 c.821G>A index patient versus right ventricular outflow tract delayed activation of a DPP6 c.2252C>T carrier. In conclusion, DPP6 variants play an important role in the mutually antagonistic regulation of I_Na and I_to, contributing to cardiac electrophysiology and arrhythmogenesis.