AbstractMany commonly consumed plants are used as folk medicines, often with unclear molecular mechanisms. Recent studies uncovered the ubiquitous and influential KCNQ family of voltage-gated potassium (Kv) channels as a therapeutic target for several medicinal plant compounds. Capers - immature flower buds of Capparis spinosa - have been consumed for food and medicinal purposes for millennia. Here, we show that caper extract hyperpolarizes cells expressing KCNQ1 or KCNQ2/3 Kv channels. Capers are the richest known natural source of quercetin, the most consumed dietary flavonoid. Quercetin potentiated KCNQ1/KCNE1, KCNQ2/3 and KCNQ4 currents but, unusually, not KCNQ5. Strikingly, quercetin augmented both activation and inactivation of KCNQ1, via a unique KCNQ activation mechanism involving sites atop the voltage sensor and in the pore. The findings uncover a novel potential molecular basis for therapeutic effects of quercetin-rich foods and a new chemical space for atypical modes of KCNQ channel modulation.