The NKP46 receptor is vital for NK cell recognition and activation against tumors, making it a target for antibody-based therapies. Humanized NKP46 mice allow for preclinical evaluation of these antibodies. A novel humanized NKP46 mouse model on the CB-17-SCID background was developed, confirming human NKP46 protein expression on NK cells. Leukocyte population analysis revealed no significant alterations compared to wild-type mice, and tumor efficacy studies demonstrated the effectiveness of anti-human NKP46 antibody treatment in reducing tumor growth. These findings highlight the suitability of humanized B-hNKP46 (CB17-SCID) mice for evaluating anti-human NKP46 antibody candidates.