Voltage-gated sodium (Na_V) and potassium (K_V) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na_Vβ1 encoded by SCN1b, an integral subunit of Na_V channels, coassembles with and modulates the biophysical properties of K_V1 and K_V7 channels, but not K_V3 channels, in an isoform-specific manner. Distinct domains of Na_Vβ1 are involved in modulation of the different K_V channels. Studies with channel chimeras demonstrate that Na_Vβ1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na_Vβ1 with the channel’s voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel’s pore domain. A molecular model based on docking studies shows Na_Vβ1 lying in the crevice between the voltage-sensing and pore domains of K_V channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na_V and K_V channels by Na_Vβ1 may promote diversity and flexibility in the overall control of cellular excitability and signaling.