Introduction: Active compounds derived from plants are able to inhibit nerve conduction. Cardamonin, a naturally occurring chalcone, manifests anti-nociceptive, anti-inflammatory and anti-neuropathy properties. Consequently, cardamonin may potentially inhibit nerve action potential, whereby, it affects the nerve conduction. Compound action potential is the sum of the activity which is measured from a nerve trunk. Objective: The study was conducted to investigate the inhibitory effect of cardamonin on compound action potentials and its possible mechanism of action on frog sciatic nerve. Methodology: Compound action potentials were recorded from frog sciatic nerve by using the AD instrument. Sciatic nerve was isolated from the frog and placed in Ringer’s solution. Stimulating electrodes were used to stimulate the nerve and recording electrodes were used to record compound action potentials. Compound action potential of the nerve were recorded before and after treatments [vehicle, cardamonin (0.5, 1 & 2 mg/ml) & morphine (3mg/ml)]. To investigate the involvement of opioidergic system, the nerve were pre-treated with naloxone and followed by cardamonin. All the data were recorded and analysed via LabTutor software. The data were analysed by using Two-way ANOVA followed by Bonferonni’s post hoc test with significant value at P < 0.05. Results: The outcomes showed that all the doses of cardamonin significantly reduced the peak amplitude of compound action potential in frog sciatic nerves. Besides, co-treatment of naloxone and cardamonin significantly (P < 0.001) reversed the effect of cardamonin on peak amplitude of compound action potential, suggesting the involvement of opioid receptors to inhibit nerve conduction. Conclusion: Cardamonin reduces the nerve signal conduction via activation of opioid receptors to modulate pain and contribute to the analgesic effects.