Nanobodies, the smallest naturally occurring antigen-binding domains, offer high stability, engineering versatility, and unique epitope accessibility, making them a promising platform for next-generation antiviral therapeutics. We report the discovery, structural elucidation, and in vivo evaluation of potent nanobodies targeting two high-priority viral pathogens: human immunodeficiency virus type 1 (HIV-1) and severe fever with thrombocytopenia syndrome virus (SFTSV). For HIV-1, we identified a highly neutralizing nanobody against the host receptor CD4 that inhibits viral entry by inducing a conformational rearrangement that prevents gp120 engagement. Engineering this molecule into a trimeric format substantially enhanced potency and breadth, achieving complete inhibition across diverse HIV-1 isolates and surpassing the clinically approved entry inhibitor Ibalizumab. In humanized mouse models, the trimeric CD4 nanobody demonstrated significant therapeutic efficacy, supporting its potential for long-acting HIV prevention and treatment.To address the urgent need for SFTSV countermeasures, we employed a heterologous immunization strategy to generate broadly neutralizing camelid nanobodies that target non-overlapping epitopes on the viral glycoprotein complex. Leveraging this epitope diversity, we designed a synergistic nanobody cocktail that achieved cross-subtype neutralization and complete viral inhibition. In humanized, lethal murine, and immunocompetent ferret models, the cocktail provided full protection and facilitated rapid viral clearance. Structural analyses defined the mechanisms underlying breadth and synergy and establish principles for nanobody-based interventions against genetically diverse bunyaviruses.These findings highlight antiviral nanobodies as a versatile therapeutic modality and advance promising candidates toward translational development for HIV-1 and SFTSV