Background <p>Topiramate (TPM) is a sulfamate-substituted monosaccharide known for its wide-ranging effects on epilepsy, neuropathic pain, and migraines. However, its precise influence on plasmalemmal ionic currents, including their magnitude and gating kinetics, remains uncertain. Therefore, a reassessment of the regulatory effect of TPM on ionic currents in electrically excitable cells is warranted.</p> Methods <p>With the aid of patch clamp technology, we investigated the effects of TPM on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from GH₃ lactotrophs.</p> Results <p>We observed that TPM exhibited a concentration-dependent inhibition of both transient (<i>I</i>_Na(T)) and late (<i>I</i>_Na(L)) components of <i>I</i>_Na, activated by brief depolarizing stimuli. At low concentration, TPM did not show any noticeable effect on <i>I</i>_Na(T); however, it was effective in reducing <i>I</i>_Na(L) amplitude. TPM caused a leftward shift in the midpoint of the steady-state inactivation curve of <i>I</i>_Na(T) without altering the gating charge. Importantly, the overall current density versus voltage relationship of <i>I</i>_Na(T) remained unaltered during TPM exposure. Intriguingly, the reduction in <i>I</i>_Na(T) induced by TPM could not be reversed by subsequent additions of flumazenil or chlorotoxin. Furthermore, TPM suppressed the density of the hyperpolarization-activated cation current (<i>I</i>_h). Simultaneously, the activation time course of <i>I</i>_h slowed in the presence of TPM. Moreover, TPM exposure decreased the hysteretic strength activated by double triangular ramp voltage, a change partially reversed by oxaliplatin. In current-clamp potential recordings, spontaneous action potentials were susceptible to suppression in the presence of TPM.</p> Conclusions <p>Collectively, these findings strongly suggest that TPM’s effects on <i>I</i>_Na and <i>I</i>_h have the potential to impact the functional activities and electrical behaviors of excitable cells.</p>