Amyloid precursor protein (APP), is commonly associated with Alzheimers disease, but its physiological function remains unknown. Nav1.6 is a key determinant of neuronal excitability in vivo. Since mouse models of gain-of-function and loss-of-function of APP and Nav1.6 share some similar phenotypes, we hypothesized that APP might be a candidate molecule for sodium channel modulation. Here, we report that APP co-localized and interacted with Nav1.6 in mouse cortical neurons. Knocking down APP decreased Nav1.6 sodium channel currents and cell surface expression. APP-induced increases in Nav1.6 cell surface expression were Go protein-dependent and were enhanced by a constitutively active Go-protein mutant and blocked by a dominant negative Go-protein mutant. APP also regulated c-Jun N-terminal kinase (JNK) activity in a Go-protein-dependent manner. JNK inhibition attenuated increases in cell surface expression of Nav1.6 sodium channels induced by overexpression of APP. JNK in turn phosphorylated APP. Nav1.6 sodium channel surface expression was increased by T668E, and decreased by T668A, mutations of APP695 mimicking and preventing T668 phosphorylation, respectively. Phosphorylation of APP695 at T668 enhanced its interaction with Nav1.6. Thus, we show that APP enhances Nav1.6 sodium channel cell surface expression through a Go-coupled JNK pathway.