Background and purpose: Postoperative pain occurs in as many as 70% of the over 230 million surgeries performed annually worldwide. Postoperative pain management still relies on opioids despite their negative consequences, resulting in a public health crisis. Therefore, it is of utmost importance to develop alternative therapies to treat chronic pain. Natural products derived from medicinal plants are potential sources of novel and are potential sources biologically active compounds for development of novel analgesics safe analgesics. Experimental approach: Hence, in this study, we screened a library of natural products to identify small molecules that target the activity of voltage-gated sodium and calcium channels due to their important roles in nociceptive sensory processing. Key Results: We found that fractions derived from the Native American medicinal plant, Parthenium incanum, inhibited depolarization-evoked calcium influx in rat dorsal root ganglion (DRG) neurons. Further separation of these fractions yielded a cycloartane-type triterpene identified as argentatin C which blocked the activity of both voltage-gated sodium and calcium channels in calcium imaging assays. Docking analysis predicted that argentatin C may bind to NaV1.7-1.9 and CaV3.1-3.3 channels. Furthermore, voltage and current clamp electrophysiology experiments showed that argentatin C decreased Na+ and T-type Ca2+ currents as well as excitability in rat and macaque DRG neurons. Consistent with these observations, argentatin C treatment reversed mechanical allodynia in a mouse model of postsurgical pain. Conclusions & Implications: The dual effect of argentatin C on voltage-gated sodium and calcium channels supports its potential as a novel treatment for painful conditions.