G-protein-gated inwardly rectifying K⁺ (GIRK) channels control various physiological functions. For example, GIRK1/2 heterotetramers in the brain regulate neuronal excitability; GIRK1/4 heterotetramers in the heart regulate heart rate. GIRK channels are potential therapeutic targets for the treatment of several diseases, such as atrial fibrillation and addiction. In the present study, we aim to identify novel agonists/antagonists of GIRK channel and its disease-causing mutants. By electrophysiological recordings using Xenopus oocytes expressing different GIRK subunits without G-protein-coupled receptors, we screened the effect of a chemical library containing hundreds of natural products on GIRK currents. We observed that some plant alkaloids inhibit the current of wild-type GIRK1/2 and GIRK1/4 channels and some other plant alkaloids strongly inhibit a neurologic disorder-causing mutant of GIRK2 channel, G156S, which locates at the selectivity filter and induces the loss of K⁺ selectivity. Our data provided us with a clue toward the elucidation of the potential of natural products as sources of novel therapeutic agents on GIRK-targeted disease.