Significance Protease-activated receptors (PARs) are G-protein–coupled receptors (GPCRs) that are activated by proteolysis and couple to multiple distinct G-proteins. Cleavage of PAR1 in endothelium stimulates either proinflammatory or antiinflammatory signaling depending on the activating protease and is important in thrombosis and inflammation. Yet the biased signaling of PAR1 has made its pharmacological modulation challenging. We show that a family of compounds, parmodulins, acts at the cytosolic face of PAR1 to differentially control G-protein coupling and stimulate cytoprotective signaling while blocking deleterious signaling. Parmodulins are antiinflammatory and antithrombotic in vivo. These compounds demonstrate the utility of targeting the cytosolic face of GPCRs to selectively modulate downstream signaling and could provide an alternative for treatment of thromboinflammatory disorders.