Dexmedetomidine is a selective α2-adrenoceptor agonist that is used because of its sedative, anxiolytic, and analgesic effects. Dexketoprofen, which is used as an analgesic, is a nonselective nonsteroidal anti-inflammatory drug (NSAID). The use of dexmedetomidine and dexketoprofen as adjuvants to local anesthetics for the peripheral nerve is gradually increasing. In this study, we aimed to investigate the effects of different doses of dexmedetomidine and dexketoprofen on conduction block of rat sciatic nerve. The isolated sciatic nerve from adult rats was transferred to a nerve chamber. The compound action potentials (CAPs) were recorded from stimulated nerve with electrophysiological methods. Dexmedetomidine (n = 8) and dexketoprofen (n = 8) were administered in the chamber with cumulative concentrations of 10-9 to 10-5 M, and the CAPs were recorded for 5 and 10 minutes. The CAP parameters were calculated. Both dexmedetomidine and dexketoprofen significantly depressed all CAP parameters in a dose-dependent manner compared with the control group, i.e., the group in which rats did not receive treatment. CAP parameters showed there was no significant difference in nerve conduction inhibition between dexmedetomidine and dexketoprofen. Higher doses of dexmedetomidine suppressed the conduction in the fast-conducting fibers; however, dexketoprofen was found to suppress the conduction in the slow-conducting fibers in a time-dependent manner and suppress the conduction in the medium- and slow-conducting fibers in a dose-dependent manner. These findings suggest that dexmedetomidine and dexketoprofen exhibit better anesthetic effects on peripheral nerve through different ways of action.