Humanized immune system (HIS) mice, which can be engrafted with human cell line-derived or patient-derived tumors, have become essential tools for preclinical and IND-enabling development of cell therapies and biologics in oncology. However, selecting the appropriate HIS model remains challenging given the diversity of humanizable mouse strains and immune-engraftment protocols. We first compared immune profiles, clinical symptoms, body weight, and survival in severely immunodeficient mice engrafted with either cord blood-derived CD34⁺ hematopoietic stem cells (HSCs) or peripheral blood mononuclear cells (PBMCs). PBMC-engrafted mice demonstrated poor survival associated with early graft-versus-host disease (GvHD) and exhibited amplification of human T cells with a partially exhausted phenotype (Lag-3⁺, TIM-3⁺). In contrast, CD34-engrafted mice showed no health deterioration over 30 weeks and developed a complete human immune system comprising T, B, NK, and myeloid cells.These results place the CD34+ HSC engrafted HIS mice as overall superior model for drug assessment as it allows a longer, GvHD-free treatment window and a more complete immune system. We next implemented a universal, irradiation-free, chemoablation-based CD34⁺ HSC-engraftment protocol to compare the extent of immune humanization across several severely immunodeficient strains, including foundational models (NOG, NCG, BNDG, BRG, and next-generation strains (NOG-EXL, which overexpresses human GM-CSF and IL-3; and FcResolv NOG, which lacks murine Fcgamma receptors). For each strain, we measured survival, overall humanization rate (percentage of human among total immune cells), and human immune-subset frequencies in blood. Finally, we demonstrate how hydrodynamic gene delivery of one or more human cytokines into HIS mice can boost certain immune populations when a transgenic strain overexpressing these cytokines is unavailable. Altogether, our findings provide a knowledge base for the selection of the humanized immune system mouse model with the most suitable immune reconstitution profile for assessing any drug candidate based on its mechanisms of action.