Lectins from different sources have been shown to interfere with HIV infection by binding to the sugars of viral‐envelope glycoproteins. Three‐dimensional atomic structures of a number of HIV‐inactivating lectins have been determined, both as free proteins and in glycan‐bound forms. However, details on the mechanism of recognition and binding to sugars are elusive. Herein we focus on the anti‐HIV lectin OAA from Oscillatoria agardhii: We show that in the absence of sugars in solution, both the sugar‐free and sugar‐bound protein conformations that were observed in the X‐ray crystal structures exist as conformational substates. Our results suggest that glycan recognition occurs by conformational selection within the ground state; this model differs from the popular “excited‐state” model. Our findings provide further insight into molecular recognition of the major receptor on the HIV virus by OAA. These details can potentially be used for the optimization and/or development of preventive anti‐HIV therapeutics.