Carisbamate (CRS, RWJ-333369) is a new anti-seizure medication. It remains unclear whether and how CRS can perturb the magnitude and/or gating kinetics of membrane ionic currents, despite a few reports demonstrating its ability to suppress voltage-gated Na+currents. In this study, we observed a set of whole-cell current recordings and found that CRS effectively suppressed the voltage-gated Na+(INa) and hyperpolarization-activated cation currents (Ih) intrinsically in electrically excitable cells (GH3cells). The effective IC50values of CRS for the differential suppression of transient (INa(T)) and lateINa(INa(L)) were 56.4 and 11.4 μM, respectively. However, CRS strongly decreased the strength (i.e., Δarea) of the nonlinear window component ofINa(INa(W)), which was activated by a short ascending ramp voltage (Vramp); the subsequent addition of deltamethrin (DLT, 10 μM) counteracted the ability of CRS (100 μM, continuous exposure) to suppressINa(W). CRS strikingly decreased the decay time constant ofINa(T)evoked during pulse train stimulation; however, the addition of telmisartan (10 μM) effectively attenuated the CRS (30 μM, continuous exposure)-mediated decrease in the decay time constant of the current. During continued exposure to deltamethrin (10 μM), known to be a pyrethroid insecticide, the addition of CRS resulted in differential suppression of the amplitudes ofINa(T)andINa(L). The amplitude ofIhactivated by a 2-s membrane hyperpolarization was diminished by CRS in a concentration-dependent manner, with an IC50value of 38 μM. ForIh, CRS altered the steady-stateI–Vrelationship and attenuated the strength of voltage-dependent hysteresis (Hys(V)) activated by an inverted isosceles-triangularVramp. Moreover, the addition of oxaliplatin effectively reversed the CRS-mediated suppression of Hys(V). The predicted docking interaction between CRS and with a model of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel or between CRS and the hNaV1.7 channel reflects the ability of CRS to bind to amino acid residues in HCN or hNaV1.7 channel via hydrogen bonds and hydrophobic interactions. These findings reveal the propensity of CRS to modifyINa(T)andINa(L)differentially and to effectively suppress the magnitude ofIh.INaandIhare thus potential targets of the actions of CRS in terms of modulating cellular excitability.