We investigated the efficacy of inhibiting persistent Na+ currents (INaP) in acute rodent models of migraine with aura. Cortical spreading depression (SD) is a slow wave of neuronal and glial depolarization that underlies the migraine aura. Minimally invasive optogenetic SD (opto-SD) causes periorbital mechanical allodynia in mice, suggesting SD activates trigeminal nociceptors. Persistent Na+ currents contribute to neuronal intrinsic excitability and have been implicated in peripheral and cortical excitation. We examined a preferential inhibitor of INaP, GS-458967, on SD-induced periorbital allodynia, SD susceptibility, and formalin-induced peripheral pain. Periorbital mechanical allodynia was tested in male and female Thy1-ChR2-YFP mice after a single opto-SD event using manual von Frey monofilaments. GS-458967 (1 mg/kg, s.c.) or vehicle was dosed immediately after opto-SD induction, and allodynia was tested 1 hour later. The electrical SD threshold and KCl-induced SD frequency were examined in the cortex in male Sprague-Dawley rats after 1 hour pretreatment with GS-458967 (3 mg/kg, s.c.) or vehicle. Effects of GS-458967 (0.5-5 mg/kg, p.o.) on spontaneous formalin hind paw behavior and locomotion were also examined in male CD-1 mice. GS-458967 suppressed opto-SD-induced periorbital allodynia and decreased susceptibility to SD. GS-458967 also diminished early and late phase formalin-induced paw-licking behavior with early phase paw licking responding to lower doses. GS-458967 up to 3 mg/kg had no impact on locomotor activity. These data provide evidence that INaP inhibition can reduce opto-SD-induced trigeminal pain behavior and support INaP inhibition as an antinociceptive strategy for both abortive and preventive treatment of migraine.