Camelid VHH/nanobodies show promise in CAR-T therapies due to their compactness and simplicity, enabling diverse targeting strategies. However, humanization and immunogenicity remain challenges. By utilizing HCAb Harbour Mice® and a novel CAR-function-based library screening platform, we identified BCMA HCAbs suitable for CAR-T therapy. The selected BCMA HCAbs exhibited specific, high binding affinity, and excellent developability. More excitingly, BCMA HCAb-based CAR-T demonstrated superior efficacy over conventional scFv-based CAR-T. These findings underscore the potential of combining fully human HCAbs with CAR-based library screening, offering innovative avenues for CAR-T cell therapies.