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Phentolamine, a non-selective α-adrenergic antagonist traditionally used for vascular conditions and local anesthetic reversal, may have properties as a modulator of pain pathways. In this study 1 using ex vivo preparations from mice, pigs, and humans, phentolamine decreased compound action potentials in a concentration-dependent manner, with a preference for C-fibers over Aδ-fibers. Notably, this effect was consistent across species, and C-fibers from NaV1.8/NaV1.9 double knockout mice exhibited reduced sensitivity to phentolamine. Patch-clamp experiments further confirmed voltage-gated sodium channel inhibition, with NaV1.8 showing the highest susceptibility. Together, these findings reveal that phentolamine’s pharmacology extends beyond adrenergic blockade, positioning it as a valuable tool for probing pain signaling pathways and a potential scaffold for the development of novel C-fiber-targeted analgesics to address chronic pain and itch disorders.