SUMMARY Dysregulation of mechanosensitive Piezo2 channels is a hallmark of mechanical allodynia, yet the cellular mechanisms that sensitize mechanoreceptors are still poorly understood. Activation of Gi-coupled receptors sensitizes Piezo2 currents, but whether Gi-coupled receptors regulate the activity of Piezo2 channels is not known. Here, we found that activation of Gi-coupled receptors potentiates Piezo2 currents in dorsal root ganglion (DRG) neurons and in heterologous systems, but inhibits Piezo1 currents in heterologous systems. The potentiation, or inhibition of Piezo currents is abolished when blocking Gβγ with the c-terminal domain of the beta-adrenergic kinase (βARKct). Pharmacological inhibition of kinases downstream of Gβγ, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), also abolished the potentiation of Piezo2 currents. Hence, our studies illustrate an indirect mechanism of action of Gβγ to sensitize Piezo2 currents after activation of Gi-coupled receptors.