Inactivation is a fundamental characteristic of Na⁺ channels, and small changes cause skeletal muscle paralysis and myotonia, epilepsy, and cardiac arrhythmia. Brain Na_v1.2a channels have faster inactivation than cardiac Na_v1.5 channels, but minor differences in inactivation gate structure are not responsible. We constructed chimeras in which the C termini beyond the fourth homologous domains of Na_v1.2a and Na_v1.5 were exchanged. Replacing the C-terminal domain (CT) of Na_v1.2a with that of Na_v1.5 (Na_v1.2/1.5CT) slowed inactivation at +40 mV ≈2-fold, making it similar to Na_v1.5. Conversely, replacing the CT of Na_v1.5 with that of Na_v1.2a (Nav1.5/1.2CT) accelerated inactivation, making it similar to Na_v1.2a. Activation properties were unaffected. The voltage dependence of steady-state inactivation of Na_v1.5 is 16 mV more negative than that of Na_v1.2a. The steady-state inactivation curve of Na_v1.2a was shifted +12 mV in Na_v1.2/1.5CT, consistent with destabilization of the inactivated state. Conversely, Na_v1.5/1.2CT was shifted −14 mV relative to Na_v1.5, consistent with stabilization of the inactivated state. Although these effects of exchanging C termini were consistent with their effects on inactivation kinetics, they magnified the differences in the voltage dependence of inactivation between brain and cardiac channels rather than transferring them. Thus, other parts of these channels determine the basal difference in steady-state inactivation. Deletion of the distal half of either the Na_v1.2 or Na_v1.5 CTs accelerated open-state inactivation and negatively shifted steady-state inactivation. Thus, the C terminus has a strong influence on kinetics and voltage dependence of inactivation in brain Na_v1.2 and cardiac Na_v1.5 channels and is primarily responsible for their differing rates of channel inactivation.