Chimeric Antigen Receptor T (CAR-T) cells represent a transformative approach in immunotherapy, utilizing engineered T lymphocytes to target cancer cells. Recent advancements have explored the use of Variable Heavy chain domain (VHH) from Camelid antibodies as the antigen-binding region in CAR-T cells, offering a compact size and unique binding properties due to its distinctive CDR3 structure. This study contrasts the therapeutic potential of VHH-based CAR-T cells against traditional single-chain variable fragment (scFv) counterparts targeting the HER-2 antigen. We engineered both single VHH and dual VHH-linked CAR-T cells, assessing their efficacy in vitro and in vivo against scFv-based CAR-T cells derived from clone 4D5. Our findings reveal that dual VHH CAR-T cells exhibit enhanced cytotoxicity in vitro and superior survival rates in vivo, despite 4D5 CAR-T cells achieving greater tumor reduction. Further, tumor-infiltrating lymphocyte (TIL) analysis highlighted phenotypic variances, with 4D5 CAR-T cells showing increased stem-like and proliferative markers, alongside higher tumor infiltration and pro-inflammatory cytokine production. Despite 4D5 CAR-T's effectiveness in tumor reduction, the improved survival rates observed with VHH-VHH CAR-T cells suggest a potentially reduced toxicity profile, marking them as a promising candidate for HER2+ cancer treatment. This study underscores the importance of exploring alternative CAR constructs to optimize therapeutic outcomes and minimize adverse effects in cancer immunotherapy.