Camelid single-domain antibody fragments (sdAbs), commonly known as VHHs or nanobodies, are emerging as versatile platforms for antiviral drug discovery due to their small size, high stability, and ability to access sterically restricted epitopes on viral surface glycoproteins. Here, we demonstrate the use of camelid animals and a camelized mouse model (nanomouse) to develop neutralizing nanobodies engineered against two globally significant pathogens, Human Immunodeficiency Virus 1 (HIV-1) and Dengue virus (DENV), to address limitations of current antiviral and antibody-based strategies. HIV-1 remains challenging to control due to its high viral genome mutation rate and heavy glycosylation of the viral envelope (Env) protein, which drive rapid immune resistance and contribute to the burden of lifelong antiretroviral therapy. Viral surface glycans shield conserved neutralizing epitopes, such as the CD4-binding site (CD4bs), preventing or delaying the generation of broadly neutralizing antibodies (bNAbs). By repeatedly immunizing alpacas with native‑like Env trimers followed by high‑throughput phage screening, we showed that bNAbs targeting the CD4‑binding site can be readily elicited and identified. Among the identified 30 distinct CD4bs-directed nanobodies, the lead candidate RSC3.Nb132 demonstrated 100% neutralization breadth with an IC50 of 0.027 µg mL⁻¹ across a 25‑virus multiclade panel. Cryo-EM structural analyses revealed CD4 mimicry and glycan-accommodating interactions underlying its potency and breadth. When formatted as a bispecific with the V2-apex-targeting bNAb CAP256V2LS, it achieved 100% breadth with a geometric mean IC50 of 0.015 µg/mL. More importantly, it maintained 92% breadth on a contemporary Tier 2 12-virus panel, outperforming related constructs. In parallel, we explored the advantage of nanobodies in mitigating DENV, a multi‑serotype flavivirus that poses major challenges for conventional antibodies. Nanobodies, which lack an antibody Fc domain, offer a strategy to neutralize virus without promoting antibody‑dependent enhancement (ADE), the driving force of severe diseases such as hemorrhagic fever caused by DENV infection. Immunization of nanomice with a stabilized DENV2 Env dimer elicited cross-neutralizing nanobodies capable of targeting multiple DENV serotypes and Zika virus. Structural modeling using AlphaFold3 indicated engagement of distinct EDII quaternary interfaces on the Env dimer. Our research demonstrates that nanobodies can be rationally elicited and engineered as next-generation therapeutics for HIV-1 and DENV.