This study describes the creation of a humanized mouse model (THX) that can mount mature, class-switched, hypermutated, and neutralizing antibody responses. THX mice were generated by grafting non-γ-irradiated, genetically myeloablated Kit^W-41^ mutant immunodeficient pups with human cord blood CD34^+^ cells and conditioning them with 17β-estradiol to promote immune cell differentiation. THX mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells, and neutrophils, and develop well-formed lymph nodes and intestinal lymphoid tissue. These mice can mount T cell-dependent and T cell-independent antibody responses, characterized by somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon vaccination with flagellin or a Pfizer-BioNTech COVID-19 mRNA vaccine, THX mice produce neutralizing antibodies against Salmonella or SARS-CoV-2 Spike S1 receptor-binding domain, with blood increments of human cytokines at physiological levels. Additionally, THX mice can develop lupus autoimmunity after pristane injection. The THX mouse model provides a platform for studying the human immune system and developing human vaccines and therapeutics.This study describes the creation of a humanized mouse model (THX) that can mount mature, class-switched, hypermutated, and neutralizing antibody responses. THX mice were generated by grafting non-γ-irradiated, genetically myeloablated Kit^W-41^ mutant immunodeficient pups with human cord blood CD34^+^ cells and conditioning them with 17β-estradiol to promote immune cell differentiation. THX mice reconstitute a human lymphoid and myeloid immune system, including marginal zone B cells, germinal center B cells, follicular helper T cells, and neutrophils, and develop well-formed lymph nodes and intestinal lymphoid tissue. These mice can mount T cell-dependent and T cell-independent antibody responses, characterized by somatic hypermutation, class-switch recombination, and plasma cell and memory B cell differentiation. Upon vaccination with flagellin or a Pfizer-BioNTech COVID-19 mRNA vaccine, THX mice produce neutralizing antibodies against Salmonella or SARS-CoV-2 Spike S1 receptor-binding domain, with blood increments of human cytokines at physiological levels. Additionally, THX mice can develop lupus autoimmunity after pristane injection. The THX mouse model provides a platform for studying the human immune system and developing human vaccines and therapeutics.