It has been more than 25 years since the avian influenza A virus (IAV) H5N1 subtype emerged in humans in 1997. Since then, this virus has become endemic in poultry and wild birds and has been causing sporadic infections in humans. Furthermore, the H5N1 subtype has undergone numerous reassortment events with other avian IAVs, resulting in the emergence of various H5Nx subtypes. Furthermore, the original H5 hemagglutinin (HA) has evolved genetically and antigenically and diversified into multiple lineages, phylogenetic clades, and subclades. In 2020, clade 2.3.4.4b H5N1 emerged in Europe and spread intercontinentally. Lately, H5N1 has exhibited a resurgence in transmission across the continents in different avian and mammalian species. Importantly, to the surprise of influenza virologists, H5N1 has recently been found to infect a new host, the cow, and has been detected in cow milk. Furthermore, spillover infections of H5N1 have also been detected in dairy farm workers. This review summarizes the recent transmission of clade 2.3.4.4b H5N1 across the globe and its pathogenesis and adaptation in different hosts. Also, this review discusses the susceptibility of the H5N1 subtype to anti-IAV drugs and vaccines and the public health response and measures that are undertaken and can be taken in the future to contain its further spread.