Introduction: Seasonal influenza vaccination, together with FDA-approved neuraminidase (NA) and polymerase acidic (PA) inhibitors, is the most effective way for prophylaxis and treatment of influenza infections. However, the low efficacy of prevailing vaccines to newly emerging influenza strains and increasing resistance to available drugs drives intense research to explore more effective inhibitors. Hemagglutinin (HA), one of the major surface proteins of influenza strains, represents an attractive therapeutic target to develop such new inhibitors. Areas covered: This review summarizes the current progress of HA-based influenza virus inhibitors and their mechanisms of action, which may facilitate further research in developing novel antiviral inhibitors for controlling influenza infections. Expert opinion: HA-mediated entry of influenza virus is an essential step for successful infection of the host, which makes HA a promising target for the development of antiviral drugs. Recent progress in delineating the crystal structures of HA, especially HA-inhibitors complexes, has revealed a number of key residues and conserved binding pockets within HA. This has opened up important insights for developing HA-based antiviral inhibitors that have a high resistance barrier and broad-spectrum activities.