Neurokinins (or tachykinins) are peptides that modulate a wide variety of human physiology through the neurokinin G protein-coupled receptor family, implicated in a diverse array of pathological processes. Here we report high-resolution crystal structures of the human NK receptor (NKR) bound to two small-molecule antagonist therapeutics - aprepitant and netupitant and the progenitor antagonist CP-99,994. The structures reveal the detailed interactions between clinically approved antagonists and NKR, which induce a distinct receptor conformation resulting in an interhelical hydrogen-bond network that cross-links the extracellular ends of helices V and VI. Furthermore, the high-resolution details of NKR bound to netupitant establish a structural rationale for the lack of basal activity in NKR. Taken together, these co-structures provide a comprehensive structural basis of NKR antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family.