The aim of this study was to evaluate the local anesthetic effects of pheniramine and diphenhydramine, two histamine H1 receptor antagonists, on spinal anesthesia and their comparison with lidocaine, a commonly used local anesthetic. After rats were injected intrathecally with diphenhydramine and pheniramine, the dose-response curves were obtained. The potency and duration of diphenhydramine and pheniramine on spinal anesthesia were compared with lidocaine. We showed that diphenhydramine and pheniramine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50) basis, the rank of potency of drugs was diphenhydramine = pheniramine > lidocaine (p < 0.05 for the differences). In equianesthetic doses (ED25, ED50, and ED75), the block duration caused by diphenhydramine was longer than that caused by pheniramine or lidocaine (p < 0.01 for the differences). Diphenhydramine, but not pheniramine or lidocaine, elicited longer duration of sensory block than that of motor block at the same dose of 1.75 μmol. These preclinical data reported that diphenhydramine with a more sensory-selective action over motor blockade demonstrated more potent and longer-lasting spinal blockades, compared with pheniramine or lidocaine.