Increased “persistent” current, caused by delayed inactivation, through voltage-gated Na⁺ (Na_V) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding to multiple sites within Na_V channel intracellular C-terminal domains (CTDs) limits persistent Na⁺ current and accelerates inactivation across the Na_V family. Arrhythmia or epilepsy mutations located in Na_V1.5 or Na_V1.2 channel CTDs, respectively, reduce CaM binding either directly or by interfering with CTD–CTD interchannel interactions. Boosting the availability of CaM, thus shifting its binding equilibrium, restores wild-type (WT)–like inactivation in mutant Na_V1.5 and Na_V1.2 channels and likewise diminishes the comparatively large persistent Na⁺ current through WT Na_V1.6, whose CTD displays relatively low CaM affinity. In cerebellar Purkinje neurons, in which Na_V1.6 promotes a large physiological persistent Na⁺ current, increased CaM diminishes the persistent Na⁺ current, suggesting that the endogenous, comparatively weak affinity of Na_V1.6 for apoCaM is important for physiological persistent current.