The influenza M2 protein is the target of the amantadine family of antiviral drugs, and its transmembrane (TM) domain structure and dynamics have been extensively studied. However, little is known about the structure of the highly conserved N-terminal ectodomain, which contains epitopes targeted by influenza vaccines. In this study, we synthesized an M2 construct containing the N-terminal ectodomain and the TM domain, to understand the site-specific conformation and dynamics of the ectodomain and to investigate the ectodomain effect on the TM structure. We incorporated 13C, 15N-labeled residues into both domains and measured their chemical shifts and linewidths using solid-state NMR. The data indicate that the entire ectodomain is unstructured and dynamic, but the motion is slower for residues closer to the TM domain. 13C lineshapes indicate that this ecto-TM construct undergoes fast uniaxial rotational diffusion, similar to the isolated TM peptide, but drug binding increases the motional rates of the TM helix while slowing down the local motion of the ectodomain residues that are close to the TM domain. Moreover, 13C and 15N chemical shifts indicate that the ectodomain shifts the conformational equilibria of the TM residues towards the drug-bound state even in the absence of amantadine, thus providing a molecular structural basis for the lower inhibitory concentration of full-length M2 compared to the ectodomain-truncated M2. We propose that this conformational selection may result from electrostatic repulsion between negatively charged ectodomain residues in the tetrameric protein. Together with the recent study of the M2 cytoplasmic domain, these results show that intrinsically disordered extramembrane domains in membrane proteins can regulate functionally relevant conformation and dynamics of the structurally ordered transmembrane domains.