The single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor A (NPR-A) or NPR1, regulates blood pressure through vasodilation and natriuresis, making it a promising therapeutic target for hypertension and heart failure. We describe two monoclonal antibodies, XX16 and REGN5308, that differentially activate GC-A. Using cryo-electron microscopy and molecular dynamics simulations, we reveal that XX16 stabilizes GC-A in an active conformation even without its ligand ANP, whereas REGN5308 requires ANP to fully promote receptor activation. Both antibodies increase ANP binding affinity to GC-A and enhance GC-A-mediated cGMP signaling, although XX16 exerts a stronger stabilizing influence on ATP and GTP binding. In a mouse model of obesity-induced hypertension, XX16 treatment significantly reduces blood pressure, underscoring its therapeutic potential. These findings outline the structural and functional basis of GC-A activation by antibody positive allosteric modulators, offering strategies for durable antihypertensive therapies and improved management of cardiovascular diseases.