<jats:p>Potassium (K<jats:sup>+</jats:sup>) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K<jats:sup>+</jats:sup>channels gated at their selectivity filter (SF), including many two-pore domain K<jats:sup>+</jats:sup>(K<jats:sub>2P</jats:sub>) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca<jats:sup>2+</jats:sup>)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K<jats:sup>+</jats:sup>occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K<jats:sup>+</jats:sup>channel activators and highlight a filter gating machinery that is conserved across different families of K<jats:sup>+</jats:sup>channels with implications for rational drug design.</jats:p>