Significance G protein-coupled receptors (GPCRs) are targeted by a large fraction of approved drugs and regulate many important cellular processes. Association of GPCRs with heterotrimeric G proteins in response to agonist activation is thought to invariably lead to G protein activation. We find instead that G ₁₂ heterotrimers can associate with agonist-bound receptors in a manner that does not lead to activation. These unproductive agonist–receptor-G protein ternary complexes sequester G ₁₂ heterotrimers and thus inhibit rather than support G ₁₂ signaling. These findings reveal a mechanism whereby agonist activation of GPCRs can inhibit as well as promote G protein signaling.