<p>Human metapneumovirus (HMPV) is a significant cause of acute respiratory tract infections, particularly in children, the elderly, and immunocompromised individuals, with no approved vaccines or antivirals available. This review provides mechanistic insights into HMPV virology, immunopathogenesis, and emerging therapeutic and vaccine strategies, bridging molecular design to translational immunity. HMPV, a member of the Pneumoviridae family, encodes nine proteins, including key surface glycoproteins F, G, and SH, which mediate attachment, fusion, and immune evasion. The virus’s life cycle involves receptor binding via integrins and glycosaminoglycans, followed by replication and assembly, with seasonal outbreaks transmitted through respiratory droplets. Immunopathogenesis highlights innate immune activation via TLRs and RIG-I-like receptors, countered by viral proteins like M2-2, leading to cytokine storms and impaired adaptive responses. Current treatments rely on supportive care, including oxygen therapy and fluid management, while investigational antivirals like ribavirin, fusion inhibitors, and monoclonal antibodies show promise, especially in severe cases. Vaccine development focuses on live-attenuated, subunit, mRNA, and virus-like particle platforms targeting the prefusion F protein for broad neutralizing immunity. Preclinical studies demonstrate enhanced immunogenicity through epitope optimization and AI-guided stabilization of antigens. Challenges include antigenic variability, waning immunity, and safety in vulnerable populations. Future directions emphasize AI-driven antigen design, pan-respiratory vaccines, and global surveillance to mitigate HMPV’s burden, estimated at millions of cases annually. This synthesis underscores the need for interdisciplinary efforts to advance prophylactic and therapeutic interventions.</p>