AbstractThe peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT₁R and its downstream signaling proteins G_q and β‐arrestin. AT₁R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT₁R β‐arrestin‐biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo‐electron microscopy (cryo‐EM) structure of the human AT₁R in complex with a balanced agonist, Sar¹‐AngII, and G_q protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT₁R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT₁R signal transduction from the ligand‐binding pocket to both G_q and β‐arrestin pathways. Specifically, we found that the MHN mutations N111^3.35A and N294^7.45A induce biased signaling to G_q and β‐arrestin, respectively. These insights should facilitate AT₁R structure‐based drug discovery for the treatment of cardiovascular diseases.