Understanding the mechanism by which ligands affect receptor conformational equilibria is key in accelerating membrane protein structural biology. In the case of G protein-coupled receptors (GPCRs), we currently pursue a brute-force approach for identifying ligands that stabilize receptors and facilitate crystallogenesis. The nociceptin/orphanin FQ peptide receptor (NOP) is a member of the opioid receptor subfamily of GPCRs for which many structurally diverse ligands are available for screening. We observed that antagonist potency is correlated with a ligand's ability to induce receptor stability (Tm) and crystallogenesis. Using this screening strategy, we solved two structures of NOP in complex with top candidate ligands SB-612111 and C-35. Docking studies indicate that while potent, stabilizing antagonists strongly favor a single binding orientation, less potent ligands can adopt multiple binding modes, contributing to their low Tm values. These results suggest a mechanism for ligand-aided crystallogenesis whereby potent antagonists stabilize a single ligand-receptor conformational pair. •A correlation is demonstrated between receptor stability and BRET functional data•Two antagonist-bound crystal structures of the N/OFQ peptide receptor are reported•Docking indicates degenerate binding modes contribute to poor receptor stabilization•A mechanism for antagonist-induced receptor stabilization is proposed Miller et al. identify a correlation between antagonist-induced receptor thermal stability and G-protein recruitment inhibition via BRET, and use this strategy to obtain two co-crystal structures of the opioid receptor NOP. Docking studies point to a mechanism for antagonist-induced receptor stabilization.