Robust humanized mouse models are critical for evaluating human hematopoietic stem cell (HSC) biology, immune system development, and therapeutic efficacy. The NCG strain provides a superior platform for human HSC engraftment due to severe immunodeficiency. To further enhance human immune system reconstitution, we engineered a next generation strain NCG-mTSLP-hIL6-mFlt3 KO. This model offers a powerful platform for human HSC engraftment and development of a functional, multi-lineage human immune system, including lymphoid (T, B), myeloid (DC subsets), and NK cells. Together with enhanced lymphoid organ development, this model is positioned to be a valuable tool for translational immunology and preclinical evaluation of immunotherapies.