The sciatic nerve has a neurotrophic activity that plays an important role in the peripheral nervous system (PNS). Compound action potentials (CAPs) is regarded as a physiological/pathological indicator to identify nerve activity in signal transduction of the PNS. Astragaloside (AST) is a small-molecule saponin, which is purified from Astragalus membranaceus. AST has been widely used to treat chronic disease. Nonetheless, the regulating effects of AST on the nerve action potential are not available. Therefore, present investigation was undertaken to study the effect of AST on CAPs of frog sciatic nerve. AST depressed the conduction velocity and amplitude of CAPs in a concentration-dependent way. Notably, the AST-induced responses could be blocked by a Ca2+-free medium as well as applying with all Ca2+ channel antagonists (CdCl2/LaCl3) or L-type Ca2+ channel blockers (nifedipine/diltiazem), but not the T-type and P-type Ca2+ channel antagonist (NiCl2). Taken together, our results suggested that AST may attenuate the CAPs of frog sciatic nerves in vitro via the L-type Ca2+-dependent mechanisms.