Influenza virus haemagglutinin (HA) binds sialic-acid receptors to mediate cell entry of canonical influenza A viruses (IAVs) and is a key determinant of viral tropism and host range. However, the bat-derived IAV subtypes H17N10 and H18N11 use uniquely the major histocompatibility complex class II molecules (MHC-II) as receptors, with their HAs unable to bind glycans. Here we combine structural, biophysical, and cellular approaches to characterize the interaction between H18 HA and the human MHC-II molecule HLA-DR. We identify a new binding site on the HA1 head domain of H18, distinct from the canonical sialic-acid-binding pocket, which mediates micromolar- affinity binding to HLA-DR. Binding of H18 to HLA-DR also induces conformational changes consistent with priming of the HA fusion machinery. Substitutions in the binding site impair HA-mediated fusion and reduce viral infectivity, while compensatory loss of a nearby HA glycosylation site restores membrane fusion and viral fitness. These findings reveal HA’s structural adaptability to engage protein receptors while retaining fusion competence, highlighting the importance of monitoring sequence variation in this MHC- II-binding region for assessing host range and adaptation potential of bat-derived IAVs.