Flufenamic acid (FFA) is a non-steroidal anti-inflammatory agent, commonly used to block non-selective cation channels. We previously reported that FFA potentiated, rather than inhibited, a cation current in Aplysia bag cell neurons. Prompted by this paradoxical result, the present study examined the effects of FFA on membrane currents and intracellular Ca²⁺ in cultured bag cell neurons. Under whole-cell voltage-clamp, FFA evoked either outward (Iout) or inward (Iin) currents. Iout had a rapid onset, was inhibited by the K⁺ channel blocker, tetraethylammonium, and was associated with both an increase in membrane conductance and a negative shift in the whole-cell current reversal potential. Iin developed more slowly, was inhibited by the cation channel blocker, Gd³⁺, and was concomitant with both an increased conductance and positive shift in reversal potential. FFA also enhanced the use-dependent inactivation and caused a positive-shift in the activation curve of the voltage-dependent Ca²⁺ current. Furthermore, as measured by ratiometric imaging, FFA produced a rise in intracellular Ca²⁺ that persisted in the absence of extracellular Ca²⁺, and was reduced by depleting either the endoplasmic reticulum and/or mitochondrial stores. Ca²⁺ appeared to be involved in the activation of Iin, as strong intracellular Ca²⁺ buffering effectively eliminated Iin, but did not alter Iout. Finally, the effects of FFA were likely not due to block of cyclooxygenase, given that the general cyclooxygenase inhibitor, indomethacin, failed to evoke either current. That FFA influences a number of neuronal properties needs to be taken into consideration when employing it as a cation channel antagonist.