First detected in poultry in China in 1996, the H5N1 avian influenza virus has evolved into a significant global public health hazard, primarily owing to its high pathogenicity and potential for interspecies transmission. While primarily affecting avian species, H5N1 has repeatedly breached species barriers, infecting mammals including humans, minks, seals, and cattle. This review synthesizes current knowledge on the molecular mechanisms underpinning H5N1´s host adaptation, focusing on key mutations in viral proteins-such as hemagglutinin (HA), neuraminidase (NA), and polymerase subunits (PB2)-which boost binding affinity to human-type receptors, increase replicative efficiency in mammalian cells, and facilitate immune evasion. Critical mutations, including HA-Q226L, HA-T199I, PB2-E627K, and NA-H274Y, are discussed in detail, highlighting their roles in altering receptor specificity, promoting antiviral resistance, and expanding viral tropism. The paper also outlines epidemiological trends, global dissemination patterns driven by migratory birds and trade, and current strategies for prevention and control, including antiviral therapeutics and vaccine development. Ultimately, this comprehensive analysis underscores the urgent need for continued surveillance, broad-spectrum countermeasures, and international collaboration to reduce the pandemic risk posed by H5N1.