The calpain superfamily of calcium-dependent papain-like cysteine proteases are highly conserved proteases that function to post-translationally modify substrates by partial proteolysis. Calpains are known to proteolyse over 100 substrates that lack strong sequence homology. Consequently, the calpain superfamily has been implicated in playing a central role in diverse physiological and pathological processes. Investigation of the physiological functions of calpains, on the one hand, and the need to develop pharmacological reagents to inhibit calpain-mediated pathological processes, on the other hand, led to the development of numerous calpain inhibitors. Using cultured Aplysia neurons and voltage clamp analysis, we report here that the calpain inhibitors calpeptin, MG132, and the calpain inhibitor XII inhibit voltage-gated potassium conductance and moderately reduce the sodium conductance. These consequently lead to spike broadening, and increased calcium influx. Such alterations of the excitable membrane properties may alter the normal patterns of neuronal and muscle electrical activities, and thus should be taken into account when evaluating the effects of calpain inhibitors as protective/therapeutic drugs, and as research tools.