Neuropathic pain is among the most common and difficult-to-treat types of chronic pain and is associated with sodium channel malfunction. The sodium channel blocker ralfinamide has exhibited potent analgesic effects in several preclinical pain models and in patients with mixed neuropathic pain syndromes (Phase II trials), but it failed to ameliorate neuropathic low back pain in Phase III trials. It is unclear whether ralfinamide is effective against neuropathic pain induced by specified etiologies. In the present study, the antinociceptive effects of ralfinamide in neuropathic pain models induced by spared nerve injury and chemotherapy were compared in a gabapentin-controlled manner. The effects of ralfinamide on physiological pain were evaluated in mechanical withdrawal, hot plate, and acetic acid writhing tests. We also investigated the effects of ralfinamide on cardiovascular function and locomotor activity. Oral ralfinamide dose-dependently alleviated spared nerve injury-induced allodynia in rats and mice. Ralfinamide increased mechanical withdrawal thresholds in oxaliplatin-induced and paclitaxel-induced neuropathic pain. Ralfinamide did not affect physiological pain, locomotion, or cardiovascular function. Together, ralfinamide attenuated mechanical allodynia in all the neuropathic pain models tested, with subtle differences in efficacy. The effect of ralfinamide is comparable to that of gabapentin, but with no interference in basal mechanical sensitivity. The present study supports the effectiveness of selective sodium channel blockade as an analgesic strategy, as well as the development of compounds similar to ralfinamide.