hERG and KCNQ channels are two classes of voltage-gated potassium (Kv) channels. Specific mutations have been identified that are causal for type II Long QT (LQT2) syndrome and neonatal epilepsy, Benign Familial Neonatal Convulsions (BFNC). Increasing evidence from clinical studies suggests that LQT2 and epilepsy coexist in some patients. Therefore, an integral approach to investigate and treat the two diseases is likely more effective. In the current study, we found NS1643 (1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea), a previously reported hERG activator, is also an activator of KCNQ channels. It potentiates the neuronal KCNQ2, KCNQ4 and KCNQ2/Q3 channels but not the cardiac KCNQ1. The effects of NS1643 on KCNQ2 channel include left shifting of V1/2 and slowing of deactivation. Analysis of dose-response curve of NS1643 revealed an EC50 value of 2.44 ± 0.25 μM. A hydrophobic phenylalanine (F137) that locates at the middle of region of the voltage-sensing domain (VSD) was identified critical for that NS1643 activity on KCNQ2. When testing NS1643 effects in rescuing LQT2 hERG mutants and the KCNQ2 BFNC mutants, we found it is particularly efficacious in some cases. Considering the substantial relationship between LQT2 and epilepsy, these findings reveal that NS1643 is a useful tool compound to elucidate the causal connection of LQT2 and epilepsy. More generally, this may provide a strategy in the development of therapeutics for LQT2 and epilepsy.